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Acute respiratory distress syndrome (ARDS) is a leading cause of COVID-19 death. Long-term metformin usage decreases COVID-19 mortality through an obscure mechanism unrelated to glycemic control. It is unclear whether and how short-term metformin-based intervention can block acute inflammation. We show that metformin inhibits IL-6 and IL-1β secretion from LPS or SARS-CoV-2 Spike protein primed macrophages undergoing NLRP3 inflammasome activation, a key to ARDS initiation. Reduced IL-6 production correlates with blunted NFAT and C/EBPβ/NFIL-6 activation, whereas inhibition of IL-1β secretion reflects interference with NLRP3 inflammasome activation. By targeting electron transfer chain complex 1, but independently of AMPK and mitophagy, metformin inhibits ATP-dependent mitochondrial DNA synthesis and blocks generation of oxidized mitochondrial DNA, a trigger of inflammasome assembly. Correspondingly, short-term metformin treatment abrogates LPS-induced ARDS, lung macrophage recruitment, damage and mortality. We suggest that metformin, a cheap and safe drug, can be used to prevent ARDS onset in COVID-19 patients. Funding: The UCSD Tissue Technology Shared Resource supported by a National Cancer Institute Cancer Center Support Grant (CCSG P30CA23100). M.A. was supported by NIH (R01AI072726). E.S-L. was supported by NIAMS (K01AR077111). Research was supported by NIH grant awards to M.K. and M.A. (U54CA260591), and M.K. (R01A1043477, P42ES010337), who is an American Cancer Research Society Professor and holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases. Conflict of Interest: M.K. is a founder of Elgia Pharmaceuticals and receives research support from Gossamer Bio and Jansen Pharmaceuticals. All other authors declare no competing interests. Ethical Approval: All mouse studies were conducted in accordance with UCSD and NIH guidelines and regulations for the housing and treatment of laboratory animals using protocols approved by the UCSD Institutional Animal Care and Use Committee.

Background Group 2 innate lymphoid cells (ILC2s) are the dominant innate lymphoid cell population in the lungs at steady state, and their release of type 2 cytokines is a central driver in responding eosinophil infiltration and increased airway hyperreactivity. Our laboratory has identified a unique subset of ILC2s in the lungs that actively produce IL-10 (ILC210s). Objective Our aim was to characterize the effector functions of ILC210s in the development and pathology of allergic asthma. Methods IL-4–stimulated ILC210s were isolated to evaluate cytokine secretion, transcription factor signaling, metabolic dependence, and effector functions in vitro. ILC210s were also adoptively transferred into Rag2–/–γc–/– mice, which were then challenged with IL-33 and assessed for airway hyperreactivity and lung inflammation. Results We have determined that the transcription factors cMaf and Blimp-1 regulate IL-10 expression in ILC210s. Strikingly, our results demonstrate that ILC210s can utilize both autocrine and paracrine signaling to suppress proinflammatory ILC2 effector functions in vitro. Further, this subset dampens airway hyperreactivity and significantly reduces lung inflammation in vivo. Interestingly, ILC210s demonstrated a metabolic dependency on the glycolytic pathway for IL-10 production, shifting from the fatty acid oxidation pathway conventionally utilized for proinflammatory effector functions. Conclusion These findings provide an important and previously unrecognized role of ILC210s in diseases associated with ILC2s such as allergic lung inflammation and asthma. They also provide new insights into the metabolism dependency of proinflammatory and anti-inflammatory ILC2 phenotypes.

Innate lymphoid cell (ILC) cytokine signatures mirror those of T helper subsets, but ILCs differ substantially as far as biological role. Tissue-resident and antigen-independent, ILCs mediate induction and resolution of inflammation, tissue homeostasis, and barrier maintenance. Although extensively character-ized in periphery, ILCs were newly identified as resident in central nervous system (CNS) meninges, and are less well-understood within this novel context. Here we show that ILC-deficient mice exhibit enhanced microglial reactivity, amplified neuroinflammatory responses and blood-brain barrier (BBB) permeability. Accordingly, transcriptomic and functional examination revealed meningeal ILC2s as vigorous interleukin (IL)-10 producers. Mechanistic relevance was demonstrated by amelioration of neuroinflammation following meningeal engraftment of adoptively-transferred wild type — but not IL-10-deficient — ILC2s. Notably, ILC2s from murine bone marrow and human blood also showed IL-10 competency, suggesting a previously-unappreciated immunoregulatory role for canonical ILC2s. Collectively, these findings reveal meningeal ILC2s as suppressors of neuroinflammation — suggesting potential for ILC2-based cell therapies in CNS pathology.

BACKGROUND: Allergic asthma is a chronic inflammatory disorder that is characterized with airway hyperreactivity (AHR) and driven by Th2 cytokine production. Group 2 innate lymphoid cells (ILC2s) secrete high amount of Th2 cytokines and contribute to the development of AHR. Autophagy is a cellular degradation pathway that recycles cytoplasmic content. However, the role of autophagy in ILC2s remains to be fully elucidated. OBJECTIVE: We characterized the effects of autophagy deficiency on ILC2 effector functions and metabolic balance. METHODS: ILC2s from autophagy deficient mice were isolated to evaluate proliferation, apoptosis, cytokine secretion, gene expression and cell metabolism. Also, autophagy deficient ILC2s were adoptively transferred into Rag(−/−)GC(−/−) mice, which were them challenged with IL-33 and assessed for airway hyperreactivity and lung inflammation. RESULTS: We demonstrate that autophagy is extensively used by activated ILC2s to maintain their homeostasis and effector functions. Deletion of the critical autophagy gene Atg5 resulted in decreased cytokine secretion and increased apoptosis. Moreover, lack of autophagy among ILC2s impaired their ability to utilize fatty acid oxidation and strikingly promoted glycolysis as evidenced by our transcriptomic and metabolite analyses. This shift of fuel dependency led to impaired homeostasis and Th2 cytokine production, thus inhibiting the development of ILC2-mediated AHR. Notably, this metabolic reprogramming was also associated with an accumulation of dysfunctional mitochondria producing excessive reactive oxygen species. CONCLUSION: These findings provide new insights into the metabolic profile of ILC2s and suggest that modulation of fuel dependency by autophagy is a potentially new therapeutic approach to target ILC2 dependent inflammation.

Objectives In this study, the cost-effectiveness of rituximab was evaluated in comparison with commonly used chemotherapy regimens for patients with advanced follicular lymphoma (FL), from the perspective of the UK National Health Service (NHS). Methods Results from four randomized controlled trials comparing the addition of rituximab to chemotherapy regimens: mitoxantrone, chlorambucil, and prednisolone (MCP); cyclophosphamide, vincristine, and prednisolone (CVP); cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP); or cyclophosphamide, etoposide, doxorubicin, prednisolone, and interferon alpha (CHVP + IFNα) versus chemotherapy alone were used to develop a Markov model. The rates of disease progression and the duration of treatment effect were obtained from the trial data. Treatments were compared in two ways: 1) an individual comparison of rituximab + chemotherapy versus chemotherapy and 2) a multiple treatment comparison using league tables. Economic and clinical outcomes (quality-adjusted life-years (QALYs)) were estimated over patient lifetimes and discounted at 3.5% per annum. Results In the individual comparison, the addition of rituximab increased QALYs by (mean, 95% confidence interval) 1.174 (1.02–1.30), 0.909 (0.79–1.01), 0.823 (0.71–0.91), and 0.453 (0.40–0.50) for MCP, CVP, CHOP, and CHVP, respectively, compared with chemotherapy alone. The incremental costs per QALY gained were £7474, £8621, £10,732, and £8551, respectively. Sensitivity analyses indicated that rituximab plus chemotherapy was a cost-effective treatment option, with incremental cost-effectiveness ratios below a threshold of £30,000 per QALY gained. When compared across the chemotherapy regimens, rituximab plus MCP appeared to be the single most cost-effective treatment option, but further randomized trials are required to substantiate this. Conclusions The addition of rituximab to chemotherapy in advanced FL was found to be highly cost-effective in the UK.