Kallikrein–Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation

Abstract

The Kallikrein–Kinin System (KKS), comprised of kallikreins (klks), bradykinins (BKs) angiotensin-converting enzyme (ACE), and many other molecules, regulates a number of physiological processes, including inflammation, coagulation, angiogenesis, and control of blood pressure. In this report, we show that KKS regulates Type I IFN responses, thought to be important in lupus pathogenesis. We used CpG (TLR9 ligand), R848 (TLR7 ligand), or recombinant IFN-α to induce interferon-stimulated genes (ISGs) and proteins, and observed that this response was markedly diminished by BKs, klk1 (tissue kallikrein), or captopril (an ACE inhibitor). BKs significantly decreased the ISGs induced by TLRs in vitro and in vivo (in normal and lupus-prone mice), and in human PBMCs, especially the induction of Irf7 gene (p < 0.05), the master regulator of Type I IFNs. ISGs induced by IFN-α were also suppressed by the KKS. MHC Class I upregulation, a classic response to Type I IFNs, was reduced by BKs in murine dendritic cells (DCs). BKs decreased phosphorylation of STAT2 molecules that mediate IFN signaling. Among the secreted pro-inflammatory cytokines/chemokines analyzed (IL-6, IL12p70, and CXCL10), the strongest suppressive effect was on CXCL10, a highly Type I IFN-dependent cytokine, upon CpG stimulation, both in normal and lupus-prone DCs. klks that break down into BKs, also suppressed CpG-induced ISGs in murine DCs. Captopril, a drug that inhibits ACE and increases BK, suppressed ISGs, both in mouse DCs and human PBMCs. The effects of BK were reversed with indomethacin (compound that inhibits production of PGE2), suggesting that BK suppression of IFN responses may be mediated via prostaglandins. These results highlight a novel regulatory mechanism in which members of the KKS control the Type I IFN response and suggest a role for modulators of IFNs in the pathogenesis of lupus and interferonopathies.

The renin–angiotensin system: An integrated view of lung disease and coagulopathy in COVID-19 and therapeutic implications

“…The increased aldosterone may be responsible for the hypokalemia seen in many COVID-19 patients. More speculatively, while the inflammatory arm of the RAS produces TNF, IL-6, and other pro-inflammatory cytokines without producing interferon, ACE cleaves bradykinin, a known suppressor of interferon, and so might lead to increased interferon in some individuals (Seliga et al, 2018). Some individuals with a particular genetic predisposition may produce high levels of interferon, and these may be the individuals who develop "COVID toes" (Landa et al, 2020;Zhang et al, 2020).…”

Centrally Acting Angiotensin-Converting Enzyme Inhibitor Suppresses Type I Interferon Responses and Decreases Inflammation in the Periphery and the CNS in Lupus-Prone Mice

“…This may not indicate that IFNα is not playing a role, but rather the ability of the IFNAR antibodies to reach the brain and affect the CNS. Our recent work (13) shows that candidates of the (28). The effect of ACEi's, especially those that can cross the BBB, on microglial activation and cognitive effects have been demonstrated recently (19).…”

“…The effects of ACEi's have been very well described to act mostly via increasing the bioavailability of BK (18). We have earlier shown in murine bone-marrow-derived dendritic cells (BMDCs) that suppression of the IFN response by BK may be brought about, in part, via prostaglandins (13). We hypothesize that ACEi's potentiate bradykinin-mediated suppression of IFN responses in vivo through prostaglandins.…”

“…Blocking IFNα or IFN receptor (IFNAR) has been tested in clinical trials with varied outcomes (11,12). We have shown recently that bradykinins (BK) and captopril [an ACE inhibitor (ACEi)] suppressed Type I IFN responses in murine dendritic cells (DCs) from normal and lupus-prone mice and in human peripheral blood mononuclear cells (PBMC) (13). We also showed that the IFN-suppressive effect of captopril in vitro was mediated, in part, via BK receptors (13).…”

Kallikrein 13: a new player in coronaviral infections

“…While one may assume that the virus stimulates KLK13 production to promote the infection, this up-regulation is likely a natural response of the damaged tissue, as KLKs were previously reported to take part also in tissue regeneration ( 87–89 ). Further, increased expression of KLKs may be the response to the inflammatory process, as Seliga et al demonstrated that KLK-kinin system is a potent modulator of innate immune responses ( 90 ).…”