We have positionally cloned the Ym1 gene, with a duplication and a promoter polymorphism, as a major regulator of inflammation. Mice with the RIIIS/J haplotype, with the absence of Ym1 expression, showed reduced susceptibility to mannan-enhanced collagen antibody–induced arthritis and to chronic arthritis induced by intranasal exposure of mannan. Depletion of lung macrophages alleviated arthritis, whereas intranasal supplement of Ym1 protein to Ym1-deficient mice reversed the disease, suggesting a key role of Ym1 for inflammatory activity by lung macrophages. Ym1-deficient mice with pneumonitis had less eosinophil infiltration, reduced production of type II cytokines and IgG1, and skewing of macrophages toward alternative activation due to enhanced STAT6 activation. Proteomics analysis connected Ym1 polymorphism with changed lipid metabolism. Induced PPAR-γ and lipid metabolism in Ym1-deficient macrophages contributed to cellular polarization. In conclusion, the natural polymorphism of Ym1 regulates alternative activation of macrophages associated with pulmonary inflammation.

Recent studies indicate that glucose metabolism is altered in rheumatoid arthritis. We hypothesize that Pkm2, as a key regulatory enzyme of glycolysis pathway, triggers the activation of macrophages (Mw), which results in proinflammatory cytokine production during the arthritis progress. In this study, Pkm2 was found to be overexpressed in ED1-positive Mw in spleens and synovial tissues from arthritic rats via immunofluorescence, Western blotting, and quantitative RT-PCR. To reveal the role of Pkm2, Dark Agouti rats were treated with either Pkm2 enzyme inhibitor shikonin or the RNA interference plasmids of Pkm2 and negative control plasmids, respectively, via i.p. injection. Pkm2 intervention could alleviate the severity of pristane-induced arthritis in aspects of the macroscopic arthritis score, perimeter changes of midpaw, and the synovitis and destruction of the bone and cartilage as well as reduce the ED1 and p-Stat1-positive cell population in rat synovial tissues. Silencing Pkm2 by RNA interference in classical activated rat and mouse Mw resulted in less Tnf-a, Il-1b production via Stat1 signaling. Collectively, Pkm2 is highly expressed in ED1-positive Mw of spleens and synovial tissues from arthritic rats and promotes Mw activation via Stat1 signaling. Pkm2 might be a promising selective metabolic target molecule for rheumatoid arthritis treatment.

MicroRNA‐147 (miR‐147) had been previously found induced in synoviocytes by inflammatory stimuli derived from T cells in experimental arthritis. This study was designed to verify whether loss of its function might alleviate inflammatory events in joints of experimental and rheumatoid arthritis (RA). Dark Agouti (DA) rats were injected intradermally with pristane to induce arthritis, and rno‐miR‐147 antagomir was locally administrated into individual ankle compared with negative control or rno‐miR‐155‐5p antagomir (potential positive control). Arthritis onset, macroscopic severity, and pathological changes were monitored. While in vitro, gain or loss function of hsa‐miR‐147b‐3p/hsa‐miR‐155‐5p and ZNF148 was achieved in human synovial fibroblast cell line SW982 and RA synovial fibroblasts (RASF). The expression of miRNAs and mRNAs was detected by using RT‐quantitative PCR, and protein expression was detected by using Western blotting. Anti‐miR‐147 therapy could alleviate the severity, especially for the synovitis and joint destruction in experimental arthritis. Gain of hsa‐miR‐147b‐3p/hsa‐miR‐155‐5p function in TNF‐α stimulated SW982 and RASF cells could upregulate, in contrast, loss of hsa‐miR‐147b‐3p/hsa‐miR‐155‐5p function could downregulate the gene expression of TNF‐α, IL‐6, MMP3, and MMP13. Hence, such alteration could participate in synovial inflammation and joint destruction. RNAi of ZNF148, a miR‐147's target, increased gene expression of TNF‐α, IL‐6, MMP3, and MMP13 in SW982 and RASF cells. Also, mRNA sequencing data showed that hsa‐miR‐147b‐3p mimic and ZNF148 siRNA commonly regulated the gene expression of CCL3 and DEPTOR as well as some arthritis and inflammation‐related pathways. Taken together, miR‐147b‐3p contributes to synovial inflammation through repressing ZNF148 in RA and experimental arthritis.

Acute respiratory distress syndrome (ARDS) is recognized as a serious public health issue that results in respiratory failure and high mortality rates. The syndrome is characterized by immune cell aggregation, communication, activation, and alveolar epithelial damage. To elucidate the complex dynamic process of the immune system’s response in ARDS, we construct the intercellular communication network of immune cells in ARDS based on a single-cell RNA sequencing dataset (including three sepsis-induced ARDS patients and four sepsis-only patients). The results show that macrophages relayed most of the intercellular signals (ligand–receptor pairs) in both groups. Many genes related to immune response (IFI44L, ISG, and HLA-DQB1) and biological functions (response to virus, negative regulation of viral life cycle, and response to interferon-beta) were detected via differentially expressed gene analysis of macrophages between the two groups. Deep analysis of the intercellular signals related to the macrophage found that sepsis-induced ARDS harbored distinctive intercellular signals related to chemokine–chemokine receptors (CCL3/4/5−CCR1), which mainly are involved in the disturbance of the STAT family transcription factors (TFs), such as STAT2 and STAT3. These signals and downstream TFs might play key roles in macrophage M1/M2 polarization in the process of sepsis-induced ARDS. This study provides a comprehensive view of the intercellular communication landscape between sepsis and sepsis-induced ARDS and identifies key intercellular communications and TFs involved in sepsis-induced ARDS. We believe that our study provides valuable clues for understanding the immune response mechanisms of ARDS.