Role of autophagy in regulating interleukin-10 and the responses to corticosteroids and statins in asthma.

Abstract

BACKGROUND:

Interleukin (IL)-10 is a key anti-inflammatory cytokine that may be reduced in asthma but is enhanced by corticosteroids, especially when combined with a statin, although the mechanisms of these effects are uncertain.

OBJECTIVE:

To study the role of autophagy in macrophages in promoting inflammation in asthma through reducing IL-10 secretion and how corticosteroids and statins may reverse this process.

METHODS:

We conducted a randomised double-blind placebo-controlled study in moderate to severe asthmatic patients (n = 44) to investigate the effect of an inhaled corticosteroid (budesonide 400 μg/day) and the combination of budesonide with an oral statin (simvastatin 10 mg/day) given for 8 weeks on autophagy protein expression in sputum cells by using immunocytochemistry and measurement of IL-10 release. In in vitro experiments, we studied cross-regulation between autophagy and IL-10 release by measuring the expression of autophagy proteins in M2-like macrophages and the effects of budesonide and simvastatin on these mechanisms.

RESULTS:

In asthmatic patients, inhaled budesonide inhibited airway macrophage autophagy (beclin-1, LC3) as well as autophagic flux (p62), which was enhanced by simvastatin and was correlated with increased sputum IL-10 and reduced IL-4 concentrations. In macrophages in vitro, budesonide and simvastatin inhibited rapamycin-induced autophagy as well as autophagic flux, with reduced expression of beclin-1 and LC3, but enhanced the accumulation of p62 and increased expression of IL-10, which itself further inhibited autophagy in macrophages. With siRNA-mediated silencing, LC3-deficient macrophages also showed a maximal induction of IL-10 transcription. Neutralisation of IL-10 with recombinant specific blocking antibody and silencing IL-10 transcription reversed the inhibitory effects of budesonide and simvastatin on macrophage autophagy.

CONCLUSION AND CLINICAL RELEVANCE:

Inhibition by corticosteroids and a statin of macrophage autophagy enhances IL-10 production, resulting in the control of asthmatic inflammation.

• Authors: Kittipong Maneechotesuwan, Kanda Kasetsinsombat, Adisak Wongkajornsilp, Peter J Barnes
• Journal: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology (Clin Exp Allergy) Vol. 51 Issue 12 Pg. 1553-1565 (12 2021) ISSN: 1365-2222 [Electronic] England
• PMID: 33423318 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 John Wiley & Sons Ltd.

Chemical References

• Adrenal Cortex Hormones
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Interleukin-10

Topics

• Administration, Inhalation
• Adrenal Cortex Hormones (pharmacology, therapeutic use)
• Asthma (drug therapy)
• Autophagy
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology, therapeutic use)
• Interleukin-10 (genetics)