Many benefits provided by the gut microbiota to the host rely on its intricate interactions with host cells. Perturbations of the gut microbiota, termed gut dysbiosis, affect the interplay between the gut microbiota and host cells, resulting in dysregulation of inflammation that contributes to the pathogenesis of chronic inflammatory diseases, including inflammatory bowel disease, multiple sclerosis, allergic asthma and rheumatoid arthritis. In this review, we provide an overview of how gut bacteria modulates host metabolic and immune functions, summarize studies that examined the roles of gut dysbiosis in chronic inflammatory diseases, and finally discuss measures to correct gut dysbiosis as potential therapeutics for chronic inflammatory diseases.

The mucosal adjuvant activity of cholera toxin depends on the microbiota, which signals through Nod2 on CD11c+ cells. Cholera toxin (CT) is a potent adjuvant for inducing mucosal immune responses. However, the mechanism by which CT induces adjuvant activity remains unclear. Here we show that the microbiota is critical for inducing antigen-specific IgG production after intranasal immunization. After mucosal vaccination with CT, both antibiotic-treated and germ-free (GF) mice had reduced amounts of antigen-specific IgG, smaller recall-stimulated cytokine responses, impaired follicular helper T (TFH) cell responses and reduced numbers of plasma cells. Recognition of symbiotic bacteria via the nucleotide-binding oligomerization domain containing 2 (Nod2) sensor in cells that express the integrin CD11c (encoded by Itgax) was required for the adjuvanticity of CT. Reconstitution of GF mice with a Nod2 agonist or monocolonization with Staphylococcus sciuri, which has high Nod2-stimulatory activity, was sufficient to promote robust CT adjuvant activity, whereas bacteria with low Nod2-stimulatory activity did not. Mechanistically, CT enhanced Nod2-mediated cytokine production in dendritic cells via intracellular cyclic AMP. These results show a role for the microbiota and the intracellular receptor Nod2 in promoting the mucosal adjuvant activity of CT.

The nuclear factor of activated T cells (NFAT5), also known as a tonicity-responsive enhancer-binding protein, was originally identified as a key transcription factor involved in maintaining cellular homeostasis against hypertonic and hyperosmotic environments. Although NFAT5 has been expressed and studied in various types of hyperosmolar tissues, evidence has emerged that NFAT5 plays a role in the development and activation of immune cells, especially T cells and macrophages. The immune-regulatory function of NFAT5 is achieved by inducing different target genes and different signaling pathways in both tonicity-dependent and -independent manners. Particularly in response to hyperosmotic stress, NFAT5 induces the generation of pathogenic T_H17 cells and pro-inflammatory macrophages, contributing to autoimmune and inflammatory diseases. Meanwhile, with tonicity-independent stimuli, including activation of the Toll-like receptors and inflammatory cytokines, NFAT5 also can be activated and promotes immune cell survival, proliferation, migration, and angiogenesis. Moreover, under isotonic conditions, NFAT5 has been implicated in the pathogenesis of a variety of inflammatory and autoimmune diseases including rheumatoid arthritis. This review describes the current knowledge of NFAT5, focusing on its immune-regulatory functions, and it highlights the importance of NFAT5 as a novel therapeutic target for chronic inflammatory diseases.

Defective apoptotic death of activated macrophages has been implicated in the pathogenesis of rheumatoid arthritis (RA). However, the molecular signatures defining apoptotic resistance of RA macrophages are not fully understood. Here, global transcriptome profiling of RA macrophages revealed that the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5) critically regulates diverse pathologic processes in synovial macrophages including the cell cycle, apoptosis, and proliferation. Transcriptomic analysis of NFAT5-deficient macrophages revealed the molecular networks defining cell survival and proliferation. Proinflammatory M1-polarizing stimuli and hypoxic conditions were responsible for enhanced NFAT5 expression in RA macrophages. An in vitro functional study demonstrated that NFAT5-deficient macrophages were more susceptible to apoptotic death. Specifically, CCL2 secretion in an NFAT5-dependent fashion bestowed apoptotic resistance to RA macrophages in vitro. Injection of recombinant CCL2 into one of the affected joints of Nfat5^+/– mice increased joint destruction and macrophage infiltration, demonstrating the essential role of the NFAT5/CCL2 axis in arthritis progression in vivo. Moreover, after intra-articular injection, NFAT5-deficient macrophages were more susceptible to apoptosis and less efficient at promoting joint destruction than were NFAT5-sufficient macrophages. Thus, NFAT5 regulates macrophage survival by inducing CCL2 secretion. Our results provide evidence that NFAT5 expression in macrophages enhances chronic arthritis by conferring apoptotic resistance to activated macrophages.

Summary: Nod‐like receptors are a family of innate immune receptors that link cytosolic sensing of microbial and danger stimuli to the activation of immune responses. Two Nod‐like receptor family members, Nod1 and Nod2, recognize bacterial peptidoglycan and activate immune responses via nuclear factor‐κB (NF‐κB) and mitogen‐activated protein kinase (MAPK). The function of Nod1 and Nod2 has been largely studied in macrophages, but the role of these receptors in other innate immune cells remains unclear. In this study, we examined the function of Nod1 and Nod2 in innate immune responses of neutrophils. Mice were injected intraperitoneally with thioglycollate, and then peritoneal neutrophils were isolated 4 hr after injection. Tri‐DAP and muramyl‐dipeptide (MDP) were used as Nod1 and Nod2 agonists, respectively. The level of cytokines [interleukin‐6 (IL‐6) and tumour necrosis factor‐α (TNF‐α)] and chemokines (CXCL1 and CCL2) was increased by MDP, but not Tri‐DAP in wild‐type (WT) neutrophils. Increased production of cytokines and chemokines with MDP was abolished in Nod2‐ and Rip2‐deficient neutrophils. MDP also induced the activation of NF‐κB and MAPK in WT neutrophils, but not in Nod2‐ and Rip2‐deficient cells. Flow cytometry analysis showed that L‐selectin shedding was induced by MDP in WT neutrophils, but not in Nod2‐ and Rip2‐deficient cells. MDP and Toll‐like receptor (TLR) agonists (Pam₃CSK₄ and lipopolysaccharide) exerted synergistic effects on the production of IL‐6 and CXCL1 in neutrophils. Moreover, Nod2 and TLR4 cooperated to produce IL‐6, TNF‐α, CXCL1 and CCL2 in neutrophils in response to Gram‐negative bacteria. Our findings suggest that the Nod2–Rip2 axis may contribute to the innate immune response of neutrophils against bacterial infection.