GM-CSF Calibrates Macrophage Defense and Wound Healing Programs during Intestinal Infection and Inflammation.

Macrophages play a central role in intestinal immunity, but inappropriate macrophage activation is associated with inflammatory bowel disease (IBD). Here, we identify granulocyte-macrophage colony stimulating factor (GM-CSF) as a critical regulator of intestinal macrophage activation in patients with IBD and mice with dextran sodium sulfate (DSS)-induced colitis. We find that GM-CSF drives the maturation and polarization of inflammatory intestinal macrophages, promoting anti-microbial functions while suppressing wound-healing transcriptional programs. Group 3 innate lymphoid cells (ILC3s) are a major source of GM-CSF in intestinal inflammation, with a strong positive correlation observed between ILC or CSF2 transcripts and M1 macrophage signatures in IBD mucosal biopsies. Furthermore, GM-CSF-dependent macrophage polarization results in a positive feedback loop that augmented ILC3 activation and type 17 immunity. Together, our data reveal an important role for GM-CSF-mediated ILC-macrophage crosstalk in calibrating intestinal macrophage phenotype to enhance anti-bacterial responses, while inhibiting pro-repair functions associated with fibrosis and stricturing, with important clinical implications.

Macrophage metabolic reprogramming presents a therapeutic target in lupus nephritis.

IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1ß, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1ß and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis.

The role of ultrasound-defined tenosynovitis and synovitis in the prediction of rheumatoid arthritis development.

OBJECTIVES: Tenosynovitis (TS) is common in early arthritis. However, the value of US-defined TS in predicting RA development is unclear. We assessed the predictive utility of US-defined TS alongside US-defined synovitis and clinical and serological variables in a prospective cohort of early arthritis patients. METHODS: One hundred and seven patients with clinically apparent synovitis of one or more joint and symptom duration ⩽3 months underwent baseline clinical, laboratory and US assessment of 19 bilateral joint sites and 16 bilateral tendon compartments. Diagnostic outcome was determined after 18 months, applying the 2010 ACR/EULAR classification criteria for RA. The predictive values of US-defined TS for persistent RA were compared with those of US-defined synovitis, clinical and serological variables. RESULTS: A total of 4066 US joint sites and 3424 US tendon compartments were included in the analysis. Forty-six patients developed persistent RA, 17 patients developed non-RA persistent disease and 44 patients had resolving disease at follow-up. US-defined TS in at least one tendon compartment at baseline was common in all groups (RA 85%, non-RA persistent disease 71% and resolving 70%). On multi-variate analysis, US-defined digit flexor TS provided independent predictive data over and above the presence of ACPA and US-defined joint synovitis. CONCLUSION: US-defined digit flexor TS provided independent predictive data for persistent RA development in patients with early arthritis. The predictive utility of this tendon site should be further assessed in a larger cohort; investigators designing imaging-based predictive algorithms for RA development should include this tendon component as a candidate variable.