IL-6 modulation for COVID-19: the right patients at the right time?

Abstract

The ongoing pandemic caused by the novel coronavirus SARS-CoV-2 has disrupted the global economy and strained healthcare systems to their limits. After the virus first emerged in late 2019, the first intervention that demonstrated significant reductions in mortality for severe COVID-19 in large-scale trials was corticosteroids. Additional options that may reduce the burden on the healthcare system by reducing the number of patients requiring intensive care unit support are desperately needed, yet no therapy has conclusively established benefit in randomized studies for the management of moderate or mild cases of disease. Severe COVID-19 disease is characterized by a respiratory distress syndrome accompanied by elevated levels of several systemic cytokines, in a profile that shares several features with known inflammatory pathologies such as hemophagocytic lymphohistiocytosis and cytokine release syndrome secondary to chimeric antigen receptor (CAR) T cell therapy. Based on these observations, modulation of inflammatory cytokines, particularly interleukin (IL)-6, was proposed as a strategy to mitigate severe disease. Despite encouraging recoveries with anti-IL-6 agents, especially tocilizumab from single-arm studies, early randomized trials returned mixed results in terms of clinical benefit with these interventions. Later, larger trials such as RECOVERY and REMAP-CAP, however, are establishing anti-IL-6 in combination with steroids as a potential option for hypoxic patients with evidence of hyperinflammation. We propose that a positive feedback loop primarily mediated by macrophages and monocytes initiates the inflammatory cascade in severe COVID-19, and thus optimal benefit with anti-IL-6 therapies may require intervention during a finite window of opportunity at the outset of hyperinflammation but before fulminant disease causes irreversible tissue damage-as defined clinically by C reactive protein levels higher than 75 mg/L.

Keywords: COVID-19; cytokines.

Figure 1

(A) Monocytic and macrophage contribution to SARS-CoV-2 hyperinflammation. SARS-CoV-2 directly infects pulmonary pneumocytes, causing cell death and the release of danger-associated molecular patterns, activating macrophages. Viral spike protein also triggers release of inflammatory cytokines, including interleukin (IL)-1β, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage inflammatory protine (MIP)-1 by alveolar-resident macrophages, promoting monocytic infiltration. Additionally, internalization of ACE2 on viral entry leads to increased angiotensin II, facilitating reactive oxygen species production, tissue damage, and an NF-κB-driven inflammatory gene expression program that includes production of chemokines, cytokines, and IL-6. (B) Contribution of IL-6 signaling to COVID-19 inflammatory cascade. Trimeric complex formation with IL-6, IL-6R and gp130 leads to dimerization and autophosphorylation of JAK1. Phosphorylated JAK1 triggers STAT3 phosphorylation and translocation to the nucleus, initiating acute-phase protein production, including chemokines, cytokines and IL-6. Phospho-JAK1 may also contribute to acute-phase transcription through an extracellular signal-regulated kinase (ERK)-dependent pathway that relies on SHP2 and Ras. Notably, IL-6 also induces expression of SOCS1 and SOC3, which negatively regulate JAK/STAT signaling. The classical signaling pathway is largely restricted to the lymphocyte compartment, where it contributes to adaptive immunity, whereas trans signaling may occur in any tissue type and is generally pro-inflammatory. Interventions that may alleviate inflammatory IL-6 signaling (ie, tocilizumab or tyrosine kinase inhibitors) are shown.