The Oxysterol Receptor EBI2 Links Innate and Adaptive Immunity to Limit IFN Response and Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with abnormal activation of the immune system. Recent attention is increasing about how aberrant lipid and cholesterol metabolism is linked together with type I interferon (IFN-I) signaling in the regulation of the pathogenesis of SLE. Here, a metabonomic analysis is performed and increased plasma concentrations of oxysterols, especially 7α, 25-dihydroxycholesterol (7α, 25-OHC), are identified in SLE patients. The authors find that 7α, 25-OHC binding to its receptor Epstein-Barr virus-induced gene 2 (EBI2) in macrophages can suppress STAT activation and the production of IFN-ß, chemokines, and cytokines. Importantly, monocytes/macrophages from SLE patients and mice show significantly reduced EBI2 expression, which can be triggered by IFN-γ produced in activated T cells. Previous findings suggest that EBI2 enhances immune cell migration. Opposite to this effect, the authors demonstrate that EBI2-deficient macrophages produce higher levels of chemokines and cytokines, which recruits and activates myeloid cells,T and B lymphocytes to exacerbate tetramethylpentadecane-induced SLE. Together, via sensing the oxysterol 7α, 25-OHC, EBI2 in macrophages can modulate innate and adaptive immune responses, which may be used as a potential diagnostic marker and therapeutic target for SLE.

HIPK2 phosphorylates HDAC3 for NF-κB acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis.

Although inflammation is critical for the clearance of pathogens, uncontrolled inflammation also contributes to the development of multiple diseases such as cancer and sepsis. Since NF-κB-mediated transactivation in the nucleus is pivotal downstream of various stimuli to induce inflammation, searching the nuclear-localized targets specifically regulating NF-κB activation will provide important therapeutic application. Here, we have identified that homeodomain-interacting protein kinase 2 (HIPK2), a nuclear serine/threonine kinase, increases its expression in inflammatory macrophages. Importantly, HIPK2 deficiency or overexpression could enhance or inhibit inflammatory responses in LPS-stimulated macrophages, respectively. HIPK2-deficient mice were more susceptible to LPS-induced endotoxemia and CLP-induced sepsis. Adoptive transfer of Hipk2+/- bone marrow cells (BMs) also aggravated AOM/DSS-induced colorectal cancer. Mechanistically, HIPK2 bound and phosphorylated histone deacetylase 3 (HDAC3) at serine 374 to inhibit its enzymatic activity, thus reducing the deacetylation of p65 at lysine 218 to suppress NF-κB activation. Notably, the HDAC3 inhibitors protected wild-type or Hipk2-/- BMs-reconstituted mice from LPS-induced endotoxemia. Our findings suggest that the HIPK2-HDAC3-p65 module in macrophages restrains excessive inflammation, which may represent a new layer of therapeutic mechanism for colitis-associated colorectal cancer and sepsis.

Necrotizing Fasciitis of the Breast: A Review of the Literature.

Background: Necrotizing fasciitis (NF) is a rare, rapidly progressing, and potentially fatal tissue infection involving subcutaneous tissue, superficial fascia, and the overlying skin. Breast NF is often misdiagnosed because of the thick breast tissue between the skin and deep fascia. Only early diagnosis followed by prompt antibiotic treatment and surgical therapy can prevent disastrous consequences. There are many case reports on breast NF, but a systematic review is lacking. Methods: Using PubMed and Scopus we performed a systematic review of the literature covering a period of 20 years. We reviewed articles with predisposing comorbidities (risk factors), triggering factors, laboratory examinations, culture of organisms, antibiotic treatment, surgical interventions, the presence of septic shock, and final outcome. We also performed statistical tests of all these factors in relation to death. Results: Forty cases identified from 38 articles were included in our literature review. Twenty-one cases (52.5%) were primary, whereas 15 cases (37.5%) occurred after surgery. In 15 cases (37.5%), the single organism responsible for NF was Streptococcus pyogenes, whereas mixed organisms were found in 17 cases (42.5%). Surgical debridement was performed in 39 (97.5%) cases. Septic shock was found in all five (12.5%) deceased cases and was associated with patient's mortality (p < 0.001). Conclusions: Breast NF is a rare, severe, and easily misdiagnosed complication. Breast NF could differ from that in other body regions in etiology pattern and clinical manifestations. Confirmed diagnosis of breast NF is based on the combination of clinical, cultural, laboratory, and imaging findings. Urgent subsequent treatments, including surgical debridement, antibiotic therapy, and reconstructive surgery, are critical for better prognosis and survival of patients.