Poroviscoelasto-plasticity of agarose-based hydrogels.

Agarose gels are excellent candidates for tissue engineering as they are tunable, viscoelastic, and show a pronounced strain-stiffening response. These characteristics make them ideal to create in vitro environments to grow cells and develop tissues. As in many other biopolymers, viscoelasticity and poroelasticity coexist as time-dependent behaviors in agarose gels. While the viscoelastic behavior of these hydrogels has been considered using both phenomenological and continuum models, there remains a lack of connection between the underlying physics and the macroscopic material response. Through a finite element analysis and complimentary experiments, we evaluated the complex time-dependent mechanical response of agarose gels in various conditions. We then conceptualized these gels as a dynamic network where the global dissociation/association rate of intermolecular bonds is described as a combination of a fast rate native to double helices forming between aligned agarose molecules and a slow rate of the agarose molecules present in the clusters. Using the foundation of the transient network theory, we developed a physics-based constitutive model that accurately describes agarose behavior. Integrating experimental results and model prediction, we demonstrated that the fast dissociation/association rate follows a nonlinear force-dependent response, whose exponential evolution agrees with Eyring's model based on the transition state theory. Overall, our results establish a more accurate understanding of the time-dependent mechanics of agarose gels and provide a model that can inform design of a variety of biopolymers with a similar network topology.

A 3D printed mimetic composite for the treatment of growth plate injuries in a rabbit model.

Growth plate injuries affecting the pediatric population may cause unwanted bony repair tissue that leads to abnormal bone elongation. Clinical treatment involves bony bar resection and implantation of an interpositional material, but success is limited and the bony bar often reforms. No treatment attempts to regenerate the growth plate cartilage. Herein we develop a 3D printed growth plate mimetic composite as a potential regenerative medicine approach with the goal of preventing limb length discrepancies and inducing cartilage regeneration. A poly(ethylene glycol)-based resin was used with digital light processing to 3D print a mechanical support structure infilled with a soft cartilage-mimetic hydrogel containing chondrogenic cues. Our biomimetic composite has similar mechanical properties to native rabbit growth plate and induced chondrogenic differentiation of rabbit mesenchymal stromal cells in vitro. We evaluated its efficacy as a regenerative interpositional material applied after bony bar resection in a rabbit model of growth plate injury. Radiographic imaging was used to monitor limb length and tibial plateau angle, microcomputed tomography assessed bone morphology, and histology characterized the repair tissue that formed. Our 3D printed growth plate mimetic composite resulted in improved tibial lengthening compared to an untreated control, cartilage-mimetic hydrogel only condition, and a fat graft. However, in vivo the 3D printed growth plate mimetic composite did not show cartilage regeneration within the construct histologically. Nevertheless, this study demonstrates the feasibility of a 3D printed biomimetic composite to improve limb lengthening, a key functional outcome, supporting its further investigation as a treatment for growth plate injuries.

Effects of Kinetic Chain Length on the Degradation of Poly(ß-amino ester)-Based Networks and Use in 3D Printing by Projection Microstereolithography.

Poly(ß-amino ester)-diacrylates (PBAE-dAs) are promising resins for three-dimensional (3D) printing. This study investigated the degradation of two PBAEs with different chemistries and kinetic chain lengths. PBAE-dA monomers were synthesized from benzhydrazide and poly(ethylene glycol) (A6) or butanediol (B6) diacrylate and then photopolymerized with pentaerythritol tetrakis(3-mercaptopropionate), which formed thiol-polyacrylate kinetic chains. This tetrathiol acts as a cross-linker and chain-transfer agent that controls the polyacrylate kinetic chain length. A6 networks exhibited bulk degradation, while B6 networks exhibited surface degradation, which transitioned to a combined surface and bulk degradation. Increasing the tetrathiol concentration shortened the polyacrylate kinetic chain and time-to-reverse gelation but degradation mode was unaffected. Hydrolysis occurred primarily through the ß-amino ester. As network hydrophilicity increased, the slower degrading ester in the thiol-polyacrylate chains contributed to degradation. Overall, this work demonstrates control over network degradation rate, mode of degradation, and time-to-reverse gelation in PBAE networks and their application in 3D printing.

The Gene Signature of Activated M-CSF-Primed Human Monocyte-Derived Macrophages Is IL-10-Dependent.

During inflammatory responses, monocytes are recruited into inflamed tissues, where they become monocyte-derived macrophages and acquire pro-inflammatory and tissue-damaging effects in response to the surrounding environment. In fact, monocyte-derived macrophage subsets are major pathogenic cells in inflammatory pathologies. Strikingly, the transcriptome of pathogenic monocyte-derived macrophage subsets resembles the gene profile of macrophage colony-stimulating factor (M-CSF)-primed monocyte-derived human macrophages (M-MØ). As M-MØ display a characteristic cytokine profile after activation (IL10high TNFlow IL23low IL6low), we sought to determine the transcriptional signature of M-MØ upon exposure to pathogenic stimuli. Activation of M-MØ led to the acquisition of a distinctive transcriptional profile characterized by the induction of a group of genes (Gene set 1) highly expressed by pathogenic monocyte-derived macrophages in COVID-19 and whose presence in tumor-associated macrophages (TAM) correlates with the expression of macrophage-specific markers (CD163, SPI1) and IL10. Indeed, Gene set 1 expression was primarily dependent on ERK/p38 and STAT3 activation, and transcriptional analysis and neutralization experiments revealed that IL-10 is not only required for the expression of a subset of genes within Gene set 1 but also significantly contributes to the idiosyncratic gene signature of activated M-MØ. Our results indicate that activation of M-CSF-dependent monocyte-derived macrophages induces a distinctive gene expression profile, which is partially dependent on IL-10, and identifies a gene set potentially helpful for macrophage-centered therapeutic strategies.

Biomimetic and mechanically supportive 3D printed scaffolds for cartilage and osteochondral tissue engineering using photopolymers and digital light processing.

Successful 3D scaffold designs for musculoskeletal tissue engineering necessitate full consideration of the form and function of the tissues of interest. When designing structures for engineering cartilage and osteochondral tissues, one must reconcile the need to develop a mechanically robust system that maintains the health of cells embedded in the scaffold. In this work, we present an approach that decouples the mechanical and biochemical needs and allows for the independent development of the structural and cellular niches in a scaffold. Using the highly tuned capabilities of digital light processing-based stereolithography, structures with complex architectures are achieved over a range of effective porosities and moduli. The 3D printed structure is infilled with mesenchymal stem cells and soft biomimetic hydrogels, which are specifically formulated with extracellular matrix analogs and tethered growth factors to provide selected biochemical cues for the guided differentiation towards chondrogenesis and osteogenesis. We demonstrate the ability to utilize these structures to (a) infill a focal chondral defect and mitigate macroscopic and cellular level changes in the cartilage surrounding the defect, and (b) support the development of a stratified multi-tissue scaffold for osteochondral tissue engineering.

Microscale Photopatterning of Through-thickness Modulus in a Monolithic and Functionally Graded 3D Printed Part.

3D printing is transforming traditional processing methods for applications ranging from tissue engineering to optics. To fulfill its maximum potential, 3D printing requires a robust technique for producing structures with precise three-dimensional (x, y and z) control of mechanical properties. Previous efforts to realize such spatial control of modulus within 3D printed parts have largely focused on low-resolution (mm to cm scale) multi-material processes and grayscale approaches that spatially vary the modulus in the x-y plane and energy dose-based (E = I 0 t exp) models that do not account for the resin's sub-linear response to irradiation intensity. Here, we demonstrate a novel approach for through-thickness (z) voxelated control of mechanical properties within a single-material, monolithic part. Control over the local modulus is enabled by a predictive model that incorporates the observed non-reciprocal dose response of the material. The model is validated by an application of atomic force microscopy to map the through-thickness modulus on multi-layered 3D parts. Overall, both smooth gradations (30 MPa change over ≈75 µm) and sharp step-changes (30 MPa change over ≈5 µm) in modulus are realized in poly(ethylene glycol) diacrylate based 3D constructs, paving the way for advancements in tissue engineering, stimuli-responsive 4D printing and graded metamaterials.

Novel Template Plasmids pCyaA'-Kan and pCyaA'-Cam for Generation of Unmarked Chromosomal cyaA' Translational Fusion to T3SS Effectors in Salmonella.

The type III secretion systems (T3SS) encoded in pathogenicity islands SPI-1 and SPI-2 are key virulence factors of Salmonella. These systems translocate proteins known as effectors into eukaryotic cells during infection. To characterize the functionality of T3SS effectors, gene fusions to the CyaA' reporter of Bordetella pertussis are often used. CyaA' is a calmodulin-dependent adenylate cyclase that is only active within eukaryotic cells. Thus, the translocation of an effector fused to CyaA' can be evaluated by measuring cAMP levels in infected cells. Here, we report the construction of plasmids pCyaA'-Kan and pCyaA'-Cam, which contain the ORF encoding CyaA' adjacent to a cassette that confers resistance to kanamycin or chloramphenicol, respectively, flanked by Flp recombinase target (FRT) sites. A PCR product from pCyaA'-Kan or pCyaA'-Cam containing these genetic elements can be introduced into the bacterial chromosome to generate gene fusions by homologous recombination using the Red recombination system from bacteriophage λ. Subsequently, the resistance cassette can be removed by recombination between the FRT sites using the Flp recombinase. As a proof of concept, the plasmids pCyaA'-Kan and pCyaA'-Cam were used to generate unmarked chromosomal fusions of 10 T3SS effectors to CyaA' in S. Typhimurium. Each fusion protein was detected by Western blot using an anti-CyaA' monoclonal antibody when the corresponding mutant strain was grown under conditions that induce the expression of the native gene. In addition, T3SS-1-dependent secretion of fusion protein SipA-CyaA' during in vitro growth was verified by Western blot analysis of culture supernatants. Finally, efficient translocation of SipA-CyaA' into HeLa cells was evidenced by increased intracellular cAMP levels at different times of infection. Therefore, the plasmids pCyaA'-Kan and pCyaA'-Cam can be used to generate unmarked chromosomal cyaA' translational fusion to study regulated expression, secretion and translocation of Salmonella T3SS effectors into eukaryotic cells.

Colecistectomía segura: ¿Qué es y cómo hacerla? ¿Cómo lo hacemos nosotros? / Safe cholecystectomy: What is it and how to do it? How do we do it?

La colecistectomía laparoscópica es uno de los procedimientos más realizados a nivel mundial. La técnica laparoscópica se considera el estándar de oro para la resolución de la patología de la vesícula biliar secundaria a litiasis, y aunque es un procedimiento seguro, no se encuentra exenta de complicaciones. La complicación más grave es la lesión de la vía biliar, que, aunque es poco frecuente, con una incidencia de 0,2 a 0,4%, conduce a una disminución en la calidad de vida y contribuye a un aumento en la morbi-mortalidad. El objetivo de este artículo es reportar nuestra técnica quirúrgica, enfatizando los principios del programa de cultura para una colecistectomía segura, propuesta y descrita por the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), para minimizar los riesgos y obtener un resultado quirúrgico satisfactorio

Laparoscopic cholecystectomy is one of the most performed procedures worldwide. The laparoscopic technique is considered the gold standard for the resolution of gallbladder pathology secondary to lithiasis, and although it is a safe procedure, it is not without complications. The most serious complication is the injury to the bile duct, which, although rare, with an incidence of 0.2% to 0.4%, leads to a decrease in quality of life and contributes to an increase in morbidity and mortality. The objective of this article is to report our surgical technique, emphaszing the principles of the program for a safe cholecystectomy, proposed and described by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), to minimize the risks and obtain a satisfactory surgical result

Image-Based Elastography of Heterochromatin and Euchromatin Domains in the Deforming Cell Nucleus.

Chromatin of the eukaryotic cell nucleus comprises microscopically dense heterochromatin and loose euchromatin domains, each with distinct transcriptional ability and roles in cellular mechanotransduction. While recent methods are developed to characterize the mechanics of nucleus, measurement of intranuclear mechanics remains largely unknown. Here, the development of "nuclear elastography," which combines microscopic imaging and computational modeling to quantify the relative elasticity of the heterochromatin and euchromatin domains, is described. Using contracting murine embryonic cardiomyocytes, nuclear elastography reveals that the heterochromatin is almost four times stiffer than the euchromatin at peak deformation. The relative elasticity between the two domains changes rapidly during the active deformation of the cardiomyocyte in the normal physiological condition but progresses more slowly in cells cultured in a mechanically stiff environment, although the relative stiffness at peak deformation does not change. Further, it is found that the disruption of the Klarsicht, ANC-1, Syne Homology domain of the Linker of Nucleoskeleton and Cytoskeleton complex compromises the intranuclear elasticity distribution resulting in elastically similar heterochromatin and euchromatin. These results provide insight into the elastography dynamics of heterochromatin and euchromatin domains and provide a noninvasive framework to further investigate the mechanobiological function of subcellular and subnuclear domains limited only by the spatiotemporal resolution of the acquired images.

Microbiota Metabolites in Health and Disease.

Metabolism is one of the strongest drivers of interkingdom interactions-including those between microorganisms and their multicellular hosts. Traditionally thought to fuel energy requirements and provide building blocks for biosynthetic pathways, metabolism is now appreciated for its role in providing metabolites, small-molecule intermediates generated from metabolic processes, to perform various regulatory functions to mediate symbiotic relationships between microbes and their hosts. Here, we review recent advances in our mechanistic understanding of how microbiota-derived metabolites orchestrate and support physiological responses in the host, including immunity, inflammation, defense against infections, and metabolism. Understanding how microbes metabolically communicate with their hosts will provide us an opportunity to better describe how a host interacts with all microbes-beneficial, pathogenic, and commensal-and an opportunity to discover new ways to treat microbial-driven diseases.

IVIg Promote Cross-Tolerance against Inflammatory Stimuli In Vitro and In Vivo.

IVIg is an approved therapy for immunodeficiency and for several autoimmune and inflammatory diseases. However, the molecular basis for the IVIg anti-inflammatory activity remains to be fully explained and cannot be extrapolated from studies on animal models of disease. We now report that IVIg impairs the generation of human monocyte-derived anti-inflammatory macrophages by inducing JNK activation and activin A production and limits proinflammatory macrophage differentiation by inhibiting GM-CSF-driven STAT5 activation. In vivo, IVIg provokes a rapid increase in peripheral blood activin A, CCL2, and IL-6 levels, an effect that can be recapitulated in vitro on human monocytes. On differentiating monocytes, IVIg promotes the acquisition of altered transcriptional and cytokine profiles, reduces TLR expression and signaling, and upregulates negative regulators of TLR-initiated intracellular signaling. In line with these effects, in vivo IVIg infusion induces a state tolerant toward subsequent stimuli that results in reduced inflammatory cytokine production after LPS challenge in human peripheral blood and significant protection from LPS-induced death in mice. Therefore, IVIg conditions human macrophages toward the acquisition of a state of cross-tolerance against inflammatory stimuli, an effect that correlates with the net anti-inflammatory action of IVIg in vivo.

Methotrexate limits inflammation through an A20-dependent cross-tolerance mechanism.

OBJECTIVES: Methotrexate (MTX) is the anchor drug for treatment of rheumatoid arthritis (RA), but the mechanism of its anti-inflammatory action is not fully understood. In RA, macrophages display a proinflammatory polarisation profile that resembles granulocyte-macrophage colony-stimulating factor (GM-CSF)-differentiated macrophages and the response to MTX is only observed in thymidylate synthase+ GM-CSF-dependent macrophages. To determine the molecular basis for the MTX anti-inflammatory action, we explored toll-like receptor (TLR), RA synovial fluid (RASF) and tumour necrosis factor receptor (TNFR)-initiated signalling in MTX-exposed GM-CSF-primed macrophages. METHODS: Intracellular responses to TLR ligands, TNFα or RASF stimulation in long-term low-dose MTX-exposed human macrophages were determined through quantitative real-time PCR, western blot, ELISA and siRNA-mediated knockdown approaches. The role of MTX in vivo was assessed in patients with arthritis under MTX monotherapy and in a murine sepsis model. RESULTS: MTX conditioned macrophages towards a tolerant state, diminishing interleukin (IL)-6 and IL-1ß production in LPS, LTA, TNFα or RASF-challenged macrophages. MTX attenuated LPS-induced MAPK and NF-κB activation, and toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF1)-dependent signalling. Conversely, MTX increased the expression of the NF-κB suppressor A20 (TNFAIP3), itself a RA-susceptibility gene. Mechanistically, MTX-induced macrophage tolerance was dependent on A20, as siRNA-mediated knockdown of A20 reversed the MTX-induced reduction of IL-6 expression. In vivo, TNFAIP3 expression was significantly higher in peripheral blood cells of MTX-responsive individuals from a cohort of patients with arthritis under MTX monotherapy, whereas MTX-treated mice exhibited reduced inflammatory responses to LPS. CONCLUSIONS: MTX impairs macrophage proinflammatory responses through upregulation of A20 expression. The A20-mediated MTX-induced innate tolerance might limit inflammation in the RA synovial context, and positions A20 as a potential MTX-response biomarker.

Serotonin drives the acquisition of a profibrotic and anti-inflammatory gene profile through the 5-HT7R-PKA signaling axis.

Peripheral serotonin (5-hydroxytryptamine, 5-HT) regulates cell growth and differentiation in numerous cell types through engagement of seven types of cell surface receptors (HTR1-7). Deregulated 5-HT/HTR levels contribute to pathology in chronic inflammatory diseases, with macrophages being relevant targets for the physio-pathological effects of 5-HT. In fact, 5-HT skews human macrophage polarization through engagement of 5-HT2BR and 5-HT7R receptors. We now report that 5-HT primes macrophages for reduced pro-inflammatory cytokine production and IFN type I-mediated signaling, and promotes an anti-inflammatory and pro-fibrotic gene signature in human macrophages. The acquisition of the 5-HT-dependent gene profile primarily depends on the 5-HT7R receptor and 5-HT7R-initiated PKA-dependent signaling. In line with the transcriptional results, 5-HT upregulates TGFß1 production by human macrophages in an HTR7- and PKA-dependent manner, whereas the absence of Htr7 in vivo results in diminished macrophage infiltration and collagen deposition in a mouse model of skin fibrosis. Our results indicate that the anti-inflammatory and pro-fibrotic activity of 5-HT is primarily mediated through the 5-HT7R-PKA axis, and that 5-HT7R contributes to pathology in fibrotic diseases.

Palmitate Conditions Macrophages for Enhanced Responses toward Inflammatory Stimuli via JNK Activation.

Obesity is associated with low-grade inflammation and elevated levels of circulating saturated fatty acids, which trigger inflammatory responses by engaging pattern recognition receptors in macrophages. Because tissue homeostasis is maintained through an adequate balance of pro- and anti-inflammatory macrophages, we assessed the transcriptional and functional profile of M-CSF-dependent monocyte-derived human macrophages exposed to concentrations of saturated fatty acids found in obese individuals. We report that palmitate (C16:0, 200 µM) significantly modulates the macrophage gene signature, lowers the expression of transcription factors that positively regulate IL-10 expression (MAFB, AhR), and promotes a proinflammatory state whose acquisition requires JNK activation. Unlike LPS, palmitate exposure does not activate STAT1, and its transcriptional effects can be distinguished from those triggered by LPS, as both agents oppositely regulate the expression of CCL19 and TRIB3 Besides, palmitate conditions macrophages for exacerbated proinflammatory responses (lower IL-10 and CCL2, higher TNF-α, IL-6, and IL-1ß) toward pathogenic stimuli, a process also mediated by JNK activation. All of these effects of palmitate are fatty acid specific because oleate (C18:1, 200 µM) does not modify the macrophage transcriptional and functional profiles. Therefore, pathologic palmitate concentrations promote the acquisition of a specific polarization state in human macrophages and condition macrophages for enhanced responses toward inflammatory stimuli, with both effects being dependent on JNK activation. Our results provide further insight into the macrophage contribution to obesity-associated inflammation.

MAFB Determines Human Macrophage Anti-Inflammatory Polarization: Relevance for the Pathogenic Mechanisms Operating in Multicentric Carpotarsal Osteolysis.

Macrophage phenotypic and functional heterogeneity derives from tissue-specific transcriptional signatures shaped by the local microenvironment. Most studies addressing the molecular basis for macrophage heterogeneity have focused on murine cells, whereas the factors controlling the functional specialization of human macrophages are less known. M-CSF drives the generation of human monocyte-derived macrophages with a potent anti-inflammatory activity upon stimulation. We now report that knockdown of MAFB impairs the acquisition of the anti-inflammatory profile of human macrophages, identify the MAFB-dependent gene signature in human macrophages and illustrate the coexpression of MAFB and MAFB-target genes in CD163+ tissue-resident and tumor-associated macrophages. The contribution of MAFB to the homeostatic/anti-inflammatory macrophage profile is further supported by the skewed polarization of monocyte-derived macrophages from multicentric carpotarsal osteolysis (Online Mendelian Inheritance in Man #166300), a pathology caused by mutations in the MAFB gene. Our results demonstrate that MAFB critically determines the acquisition of the anti-inflammatory transcriptional and functional profiles of human macrophages.

Reshaping of Human Macrophage Polarization through Modulation of Glucose Catabolic Pathways.

Macrophages integrate information from the tissue microenvironment and adjust their effector functions according to the prevalent extracellular stimuli. Therefore, macrophages can acquire a variety of activation (polarization) states, and this functional plasticity allows the adequate initiation, regulation, and resolution of inflammatory responses. Modulation of the glucose metabolism contributes to the macrophage adaptation to the surrounding cytokine milieu, as exemplified by the distinct glucose catabolism of macrophages exposed to LPS/IFN-γ or IL-4. To dissect the acquisition of macrophage effector functions in the absence of activating cytokines, we assessed the bioenergetic profile of macrophages generated in the presence of GM-CSF (GM-MØ) or M-CSF (M-MØ), which do not release pro- or anti-inflammatory cytokines unless subjected to additional activating stimuli. Compared to M-MØ, GM-MØ displayed higher oxygen consumption rate and aerobic glycolysis (extracellular acidification rate [ECAR]), as well as higher expression of genes encoding glycolytic enzymes. However, M-MØ exhibited a significantly higher oxygen consumption rate/ECAR ratio. Surprisingly, whereas aerobic glycolysis positively regulated IL1B, TNF, and INHBA mRNA expression in both macrophage subtypes, mitochondrial respiration negatively affected IL6, IL1B, TNF, and CXCL10 mRNA expression in M-MØ. The physiological significance of these results became evident under low oxygen tensions, as hypoxia enhanced ECAR in M-MØ via HIF-1α and HIF-2α, increased expression of glycolytic enzymes and GM-MØ-specific genes, and diminished expression of M-MØ-associated genes. Therefore, our data indicate that GM-MØ and M-MØ display distinct bioenergetic profiles, and that hypoxia triggers a transcriptomic switch in macrophages by promoting a HIF-1α/HIF-2α-dependent increase in ECAR.

Human adipose tissue-derived mesenchymal stromal cells promote B-cell motility and chemoattraction.

BACKGROUND AIMS: Mesenchymal stromal cells hold special interest for cell-based therapy because of their tissue-regenerative and immunosuppressive abilities. B-cell involvement in chronic inflammatory and autoimmune pathologies makes them a desirable target for cell-based therapy. Mesenchymal stromal cells are able to regulate B-cell function; although the mechanisms are little known, they imply cell-to-cell contact. METHODS: We studied the ability of human adipose tissue-derived mesenchymal stromal cells (ASCs) to attract B cells. RESULTS: We show that ASCs promote B-cell migration through the secretion of chemotactic factors. Inflammatory/innate signals do not modify ASC capacity to mediate B-cell motility and chemotaxis. Analysis of a panel of B cell-related chemokines showed that none of them appeared to be responsible for B-cell motility. Other ASC-secreted factors able to promote cell motility and chemotaxis, such as the cytokine interleukin-8 and prostaglandin E2, did not appear to be implicated. CONCLUSIONS: We propose that ASC promotion of B-cell migration by undefined secreted factors is crucial for ASC regulation of B-cell responses.

Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer.

The receptor tyrosine kinases Axl and Mer, belonging to the Tyro3, Axl and Mer (TAM) receptor family, are expressed in a number of tumor cells and have well-characterized oncogenic roles. The therapeutic targeting of these kinases is considered an anticancer strategy, and various inhibitors are currently under development. At the same time, Axl and Mer are expressed in dendritic cells and macrophages and have an essential function in limiting inflammation. Inflammation is an enabling characteristic of multiple cancer hallmarks. These contrasting oncogenic and anti-inflammatory functions of Axl and Mer posit a potential paradox in terms of anticancer therapy. Here we demonstrate that azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced inflammation-associated cancer is exacerbated in mice lacking Axl and Mer. Ablation of Axl and Mer signaling is associated with increased production of proinflammatory cytokines and failure to clear apoptotic neutrophils in the intestinal lamina propria, thereby favoring a tumor-promoting environment. Interestingly, loss of these genes in the hematopoietic compartment is not associated with increased colitis. Axl and Mer are expressed in radioresistant intestinal macrophages, and the loss of these genes is associated with an increased inflammatory signature in this compartment. Our results raise the possibility of potential adverse effects of systemic anticancer therapies with Axl and Mer inhibitors, and underscore the importance of understanding their tissue and cell type-specific functions in cancer.