Lupus-prone NZM2328 mice exhibit enhanced UV-induced myeloid cell recruitment and activation in a type I interferon dependent manner.

Though the exact causes of systemic lupus erythematosus (SLE) remain unknown, exposure to ultraviolet (UV) light is one of the few well-known triggers of cutaneous inflammation in SLE. However, the precise cell types which contribute to the early cutaneous inflammatory response in lupus, and the ways that UV dosing and interferons modulate these findings, have not been thoroughly dissected. Here, we explore these questions using the NZM2328 spontaneous murine model of lupus. In addition, we use iNZM mice, which share the NZM2328 background but harbor a whole-body knockout of the type I interferon (IFN) receptor, and wild-type BALB/c mice. 10-13-week-old female mice of each strain were treated with acute (300 mJ/cm2 x1), chronic (100 mJ/cm2 daily x5 days), or no UVB, and skin was harvested and processed for bulk RNA sequencing and flow cytometry. We identify that inflammatory pathways and gene signatures related to myeloid cells - namely neutrophils and monocyte-derived dendritic cells - are a shared feature of the acute and chronic UVB response in NZM skin greater than iNZM and wild-type skin. We also verify recruitment and activation of these cells by flow cytometry in both acutely and chronically irradiated NZM and WT mice and demonstrate that these processes are dependent on type I IFN signaling. Taken together, these data indicate a skewed IFN-driven inflammatory response to both acute and chronic UVB exposure in lupus-prone skin dominated by myeloid cells, suggesting both the importance of type I IFNs and myeloid cells as therapeutic targets for photosensitive patients and highlighting the risks of even moderate UV exposure in this patient population.

Capping protein regulator and myosin 1 linker 3 regulates transcription of key cytokines in activated phagocytic cells.

We have recently reported that capping protein regulator and myosin 1 linker 3 (CARMIL3), first identified as an oncofetal-like gene, is required for metastasis of breast and prostate cancer cells via regulating the actin cytoskeletal dynamics near the plasma membrane. Here, we demonstrate a novel function of CARMIL3 as an essential regulator of the transcription of several key proinflammatory cytokines in macrophages engulfing apoptotic cells and/or exposed to lipopolysaccharides (LPS). CARMIL3-deficient macrophages expressed strongly abrogated levels of interleukin (IL)-6, TNF-α, IL-1ß and IL-23 in response to LPS, whereas IL-10 expression was enhanced. An RNA-seq analysis of CARMIL3-deficient and wild-type (WT) RAW264.7 cells stimulated with LPS revealed many differentially expressed genes, impacting several important inflammatory pathways. At the molecular level, CARMIL3 deficiency caused a strong impairment in LPS-activated nuclear factor-κB (NF-κB) signaling with decreased IKKα/ß and IκBα phosphorylation and severely reduced p65 protein levels. This study uncovers a crucial role of CARMIL3 in impacting the balance between inflammation and tissue homeostasis via regulating major cytokines production in phagocytic cells.

The potential similarities of COVID-19 and autoimmune disease pathogenesis and therapeutic options: new insights approach.

Cytokine pathways and their signaling disorders can be the cause of onset and pathogenesis of many diseases such as autoimmune diseases and COVID-19 infection. Autoimmune patients may be at higher risk of developing infection due to the impaired immune responses, the use of immunosuppressive drugs, and damage to various organs. Increased secretion of inflammatory cytokines and intolerance of the patient's immune system to COVID-19 infection are the leading causes of hospitalization of these patients. The content used in this paper has been taken from English language articles (2005-2020) retrieved from the PubMed database and Google Scholar search engine using "COVID-19," "Autoimmune disease," "Therapeutic," "Pathogenesis," and "Pathway" keywords. The emergence of COVID-19 and its association with autoimmune disorders is a major challenge in the management of these diseases. The results showed that the use of corticosteroids in the treatment of autoimmune diseases can make diagnosis and treatment of COVID-19 more challenging by preventing the fever. Due to the common pathogenesis of COVID-19 and autoimmune diseases, the use of autoimmune drugs as a possible treatment option could help control the virus. KEY POINTS: • Inflammatory cytokines play an essential role in the pathogenesis of COVID-19 • ACE2 dysfunctions are related to the with COVID-19 and autoimmune diseases • The use autoimmune diseases drugs can be useful in treating COVID-19.

Immunoproteasome inhibitor DPLG3 attenuates experimental colitis by restraining NF-κB activation.

Inflammatory bowel disease is a chronic and pathologic autoimmune condition. And immunoproteasome is becoming an attractive therapeutic target for autoimmune inflammatory diseases. In this study, we evaluated the therapeutic effects of a specific small molecule inhibitor of the chymotryptic-like ß5i subunits of the immunoproteasome, DPLG3, in a preclinical murine colitis model and explored the underlying molecular mechanism for the immune suppression. DPLG3 showed significant effects in attenuating the disease progression in experimental colitis, reducing the body and spleen weight losses, and colon length shortening compared to vehicle-treated controls and to the well studied immunoproteasome inhibitor ONX-0914. Mechanistically, DPLG3 decreased inflammatory cytokines and the influx of effector T cells and macrophages in colon tissues while increasing the number of regulatory T cells. Molecular docking analysis of the protein-ligand interaction profile revealed that the ß5i-DPLG3 complex was more stable and efficient in the binding sites compared to those formed with ONX-0914 and LU-005i. Furthermore, DPLG3 reduced the protein levels of the canonical NF-κB p50 and p65, as well as the nuclear p65. Thus, DPLG3 constitutes a potentially efficacious clinical agent for autoimmune inflammatory diseases.