How Does MCPIP1 Suppress Intestinal Inflammation via the Atf3-Ap1s2 Signaling Pathway?

Inflammatory bowel disease (IBD) is a recurrent chronic non-specific intestinal inflammatory disorder whose pathogenesis remains incompletely understood. Current research suggests that IBD may be closely associated with abnormal mucosal immune responses, impaired intestinal barrier function, genetic susceptibility, gut microbiota dysbiosis, and environmental factors. Inflamed intestinal mucosa contains a large number of activated immune cells, and biological agents targeting immune cells and pro-inflammatory cytokines have become an important strategy for IBD treatment. However, the immune effector mechanisms of monocytes and macrophages in the initiation and progression of IBD require further investigation, making this area a focal point in global IBD research.

Professor Liu Zhanju’s team from Tongji University published a research paper titled *“MCPIP1 restrains mucosal inflammation by orchestrating the intestinal monocyte to macrophage maturation via an ATF3-AP1S2 axis”* in the journal Gut. The study reveals that MCPIP1 plays a key role in regulating intestinal mucosal inflammation by influencing the maturation of monocytes into macrophages through the Atf3-Ap1S2 signaling pathway.

1. What Are the Origin and Differentiation Process of Macrophages?

Macrophages can originate from the yolk sac, fetal liver, or hematopoietic stem cells. Under physiological conditions, monocytes in the peripheral blood highly express CCR2 and migrate to tissues or lymph nodes under the guidance of the chemokine MCP-1 (CCL2). They undergo four typical differentiation stages (P1 to P4) to mature into macrophages, which then reside in the intestine and participate in maintaining intestinal mucosal immune homeostasis. Macrophages at the P3 and P4 stages exhibit strong anti-inflammatory and bactericidal functions. However, during intestinal inflammation, the differentiation of monocytes into macrophages is blocked, stagnating at the P1/P2 stages. This leads to the release of large amounts of pro-inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α) and chemokines (e.g., CCL2, CCL3, CCL4), exacerbating the inflammatory response. Mature macrophages possess high plasticity and can polarize into pro-inflammatory (M1) or anti-inflammatory (M2) types under different microenvironments, performing distinct immune functions. Therefore, elucidating the regulatory mechanisms of monocyte maturation障碍 and macrophage polarization is crucial for understanding the immunopathological mechanisms of IBD.

2. How Does MCPIP1 Deficiency Affect Intestinal Inflammation?

The research team used myeloid cell-specific MCPIP1 knockout (Mcpip1∆Mye) mice and found that these mice developed spontaneous inflammation in multiple organs, with the intestines exhibiting epithelial barrier damage and extensive immune cell infiltration. In DSS/TNBS-induced acute colitis models, this phenotype was further aggravated, accompanied by enhanced migration of myeloid cells, blocked monocyte-to-macrophage maturation (increased P1 cells, decreased P3/P4 cells), and elevated levels of pro-inflammatory cytokines.

Using single-cell sequencing to classify CD11b⁺ myeloid cells in the intestinal lamina propria, the researchers identified five subsets and observed a significant increase in two P1-like cell populations and a decrease in one P3/P4-like population in Mcpip1∆Mye mice. Notably, a subset of cells expressing Ccr2, Il-1β, Tlr2, and Ly6c but not Cx3cr1, Cd163, or Mrc1 exhibited strong pro-inflammatory characteristics, which may be a key factor exacerbating inflammation.

3. How Does MCPIP1 Regulate Macrophages via the Atf3-Ap1s2 Axis?

By integrating RNA sequencing, single-cell sequencing, and RIP-seq data, the study found that MCPIP1 deficiency led to increased expression of Atf3 and Ap1s2. Luciferase reporter assays, CUT&TAG, and Western blot experiments confirmed that Atf3 directly binds to the Ap1s2 promoter region and promotes its transcription, while MCPIP1 inhibits this pathway.

In vitro experiments showed that inhibiting Atf3 or Ap1s2 expression promoted M2 polarization of bone marrow-derived macrophages (BMDMs) and reduced their migration ability. In vivo inhibition of Ap1s2 alleviated the colitis phenotype in Mcpip1∆Mye mice, reduced myeloid cell infiltration, and improved monocyte maturation blockage (decreased P1, increased P3/P4).

4. What Are the Implications of This Study for Clinical Diagnosis and Treatment of IBD?

The researchers observed elevated MCPIP1 expression in peripheral blood CD14⁺ cells and intestinal mucosal tissues of IBD patients, suggesting that MCPIP1 may participate in the disease process as a negative feedback regulator. In vitro culture of human CD14⁺-derived macrophages with inhibited Atf3 or Ap1s2 similarly enhanced M2 polarization, indicating that targeting this signaling pathway may have anti-inflammatory and immunomodulatory effects.

This study systematically elucidates a novel mechanism by which MCPIP1 regulates monocyte-macrophage maturation and polarization via the Atf3-Ap1s2 signaling axis. It not only deepens the understanding of IBD immunopathology but also provides a theoretical basis for developing therapeutic strategies targeting Ap1s2.