Effects of Non-steroidal Anti-inflammatory Drugs (NSAIDs) and Gastroprotective NSAIDs on the Gastrointestinal Tract: A Narrative Review.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for their anti-inflammatory, antipyretic, and analgesic properties. However, their use is often associated with gastrointestinal tract (GIT) side effects due to the inhibition of both cyclooxygenase (COX)-1 and COX-2 enzymes, leading to a decrease in gastroprotective prostaglandins (PG). To minimize these adverse effects, various approaches have been explored, including selective COX-2 inhibitors, NO-NSAIDs (nitric oxide-releasing NSAIDs), and dual COX/LOX (lipoxygenase) NSAIDs. However, the effects of these gastroprotective NSAIDs on the GIT and their efficacy remains uncertain. This review aims to provide an overview of the current understanding of the effects of traditional NSAIDs and gastroprotective NSAIDs on GIT. We discuss the underlying mechanisms of GIT damage caused by NSAIDs, including mucosal injury, ulceration, and bleeding, and the potential of gastroprotective NSAIDs to mitigate these effects. We also summarize recent studies on the efficacy and safety of various gastroprotective NSAIDs and highlight the limitations and challenges of these approaches. The review concludes with recommendations for future research in this field.

Regulation of Intrinsic and Bystander T Follicular Helper Cell Differentiation and Autoimmunity by Tsc1.

T Follicular helper (Tfh) cells promote germinal center (GC) B cell responses to develop effective humoral immunity against pathogens. However, dysregulated Tfh cells can also trigger autoantibody production and the development of autoimmune diseases. We report here that Tsc1, a regulator for mTOR signaling, plays differential roles in Tfh cell/GC B cell responses in the steady state and in immune responses to antigen immunization. In the steady state, Tsc1 in T cells intrinsically suppresses spontaneous GC-Tfh cell differentiation and subsequent GC-B cell formation and autoantibody production. In immune responses to antigen immunization, Tsc1 in T cells is required for efficient GC-Tfh cell expansion, GC-B cell induction, and antigen-specific antibody responses, at least in part via promoting GC-Tfh cell mitochondrial integrity and survival. Interestingly, in mixed bone marrow chimeric mice reconstituted with both wild-type and T cell-specific Tsc1-deficient bone marrow cells, Tsc1 deficiency leads to enhanced GC-Tfh cell differentiation of wild-type CD4 T cells and increased accumulation of wild-type T regulatory cells and T follicular regulatory cells. Such bystander GC-Tfh cell differentiation suggests a potential mechanism that could trigger self-reactive GC-Tfh cell/GC responses and autoimmunity via neighboring GC-Tfh cells.

Differential controls of MAIT cell effector polarization by mTORC1/mTORC2 via integrating cytokine and costimulatory signals.

Mucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage differentiation remain unclear. Here, we report that IL-2/IL-15 receptor ß chain and inducible costimulatory (ICOS) not only serve as lineage-specific markers for IFN-γ-producing MAIT1 and IL-17A-producing MAIT17 cells, but are also important for their differentiation, respectively. Both IL-2 and IL-15 induce mTOR activation, T-bet upregulation, and subsequent MAIT cell, especially MAIT1 cell, expansion. By contrast, IL-1ß induces more MAIT17 than MAIT1 cells, while IL-23 alone promotes MAIT17 cell proliferation and survival, but synergizes with IL-1ß to induce strong MAIT17 cell expansion in an mTOR-dependent manner. Moreover, mTOR is dispensable for early MAIT cell development, yet pivotal for MAIT cell effector differentiation. Our results thus show that mTORC2 integrates signals from ICOS and IL-1ßR/IL-23R to exert a crucial role for MAIT17 differentiation, while the IL-2/IL-15R-mTORC1-T-bet axis ensures MAIT1 differentiation.