HIF-1α is a negative regulator of interferon regulatory factors: Implications for interferon production by hypoxic monocytes.

Patients with severe COVID-19 infection exhibit a low level of oxygen in affected tissue and blood. To understand the pathophysiology of COVID-19 infection, it is therefore necessary to understand cell function during hypoxia. We investigated aspects of human monocyte activation under hypoxic conditions. HMGB1 is an alarmin released by stressed cells. Under normoxic conditions, HMGB1 activates interferon regulatory factor (IRF)5 and nuclear factor-κB in monocytes, leading to expression of type I interferon (IFN) and inflammatory cytokines including tumor necrosis factor α, and interleukin 1ß, respectively. When hypoxic monocytes are activated by HMGB1, they produce proinflammatory cytokines but fail to produce type I IFN. Hypoxia-inducible factor-1α, induced by hypoxia, functions as a direct transcriptional repressor of IRF5 and IRF3. As hypoxia is a stressor that induces secretion of HMGB1 by epithelial cells, hypoxia establishes a microenvironment that favors monocyte production of inflammatory cytokines but not IFN. These findings have implications for the pathogenesis of COVID-19.

HMGB1-C1q complexes regulate macrophage function by switching between leukotriene and specialized proresolving mediator biosynthesis.

Macrophage polarization is critical to inflammation and resolution of inflammation. We previously showed that high-mobility group box 1 (HMGB1) can engage receptor for advanced glycation end product (RAGE) to direct monocytes to a proinflammatory phenotype characterized by production of type 1 IFN and proinflammatory cytokines. In contrast, HMGB1 plus C1q form a tetramolecular complex cross-linking RAGE and LAIR-1 and directing monocytes to an antiinflammatory phenotype. Lipid mediators, as well as cytokines, help establish a milieu favoring either inflammation or resolution of inflammation. This study focuses on the induction of lipid mediators by HMGB1 and HMGB1 plus C1q and their regulation of IRF5, a transcription factor critical for the induction and maintenance of proinflammatory macrophages. Here, we show that HMGB1 induces leukotriene production through a RAGE-dependent pathway, while HMGB1 plus C1q induces specialized proresolving lipid mediators lipoxin A4, resolvin D1, and resolvin D2 through a RAGE- and LAIR-1-dependent pathway. Leukotriene exposure contributes to induction of IRF5 in a positive-feedback loop. In contrast, resolvins (at 20 nM) block IRF5 induction and prevent the differentiation of inflammatory macrophages. Finally, we have generated a molecular mimic of HMGB1 plus C1q, which cross-links RAGE and LAIR-1 and polarizes monocytes to an antiinflammatory phenotype. These findings may provide a mechanism to control nonresolving inflammation in many pathologic conditions.

Sentinel Lymph Node Biopsy Versus Elective Node Dissection in Stage cT1-2N0 Oral Cavity Cancer.

OBJECTIVE: To compare overall survival (OS) and disease-free survival (DFS) between sentinel lymph node biopsy (SNB) and elective neck dissection (END) in the surgical management of cT1-2N0 oral cavity squamous cell carcinoma (OCSCC). METHODS: English full-text articles were searched in PubMed and Embase on May 9, 2021. Articles had to compare SNB with END in cT1-T2N0 OCSCC patients; report hazard ratios (HRs), Kaplan-Meier curves, or P-values with total number of events for survival outcomes; be from a clinical trial, cohort, or case-control study. Two reviewers reviewed articles and a third settled disagreements. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Risk of Bias in Non-randomized Studies of Interventions tool and revised Cochrane risk-of-bias tool for randomized trials were used. The generic inverse variance method with a random-effect model was used for meta-analysis. RESULTS: Ten studies, five retrospective, three prospective, and two randomized controlled trials, were included (total number of patients [n] = 10,498, END n = 9102, SNB n = 1396). No significant differences were found in OS (HR = 0.92; 95% confidence interval [CI]: 0.65-1.31) or DFS (HR = 0.70; 95% CI: 0.41-1.20). Heterogeneity was not detected in pooled OS analysis (P = .18; I2  = 30%), but was in pooled DFS analysis (P = .003; I2  = 66%). CONCLUSIONS: No statistically significant differences in OS or DFS were observed between SNB and END in cT1-2N0 OCSCC, suggesting that SNB might be an alternative to END in the management of early-stage, clinically node-negative OCSCC. Laryngoscope, 132:989-998, 2022.