Interferon-γ regulates cardiac myeloid cells in myocardial infarction

This editorial refers to ‘A sequential interferon gamma directed chemotactic cellular immune response determines survival and cardiac function post-myocardial infarction’, by S. Finger et al., pp. 1907–1917.

Interferons’ interferences with viral replication were discovered more than 60 years ago.¹ Today, we know that interferons (IFNs) are involved in a multitude of processes in innate and adaptive immunity.² At least seven different IFNs have been found in humans, and these cytokines are generally divided into two categories contingent on receptor affinity and sequence homology.^2,3 Type 1 IFNs, such as IFN-α and IFN-β, activate IFN-α-receptor which is expressed by a wide gamut of cells.^4,5 While most cells are able to release type 1 IFNs, IFN-α is predominantly released by leucocytes and IFN-β by fibroblasts.^2,5 Transcriptional changes upon receptor activation hinder viral replication in healthy and virus-infected cells.⁵ In contrast to several type 1 IFNs that act via IFN-α-receptor, IFN-γ is the only type 2 IFN. Different lymphocytes and natural killer cells are the main source for this cytokine.² IFN-γ-receptor activity is regulated through the receptor’s inducible β-chain.² IFN-γ signalling primes lymphoid and myeloid cells such as macrophages. For instance, IFN-γ enhances antigen presentation via up-regulation of MHCII and fortifies alveolar macrophages against a secondary bacterial infection.⁶ Next to interferon’s function in infectious disease, evidence for a regulatory role in cardiovascular disease is accumulating.^7,8 Hope for cardiovascular immunotherapy is further fuelled by the first-in-man trial in atherosclerotic patients with residual inflammatory risk after myocardial infarction that benefited from interleukin-1β antagonism using the monoclonal antibody canakinumab.⁹

In myocardial infarction, the acute inflammatory phase is characterized by neutrophilic granulocytes rapidly infiltrating the ischaemic myocardium. Inflammatory Ly6C^high monocytes follow shortly after.^10,11 Monocyte-derived macrophages drive inflammation in the ischaemic tissue in the next couple days after myocardial infarction. Distinct macrophage subsets particularly harm the ischaemic myocardium, a mechanism that relies on type 1 IFN dependent inflammation.⁷ Later on, transcriptional changes in macrophages foster resolution of inflammation and scar formation.¹⁰ While many signals regulating different stages after myocardial infarction have been uncovered, the role of IFN-γ in this setting remained largely unknown. Finger et al. describe for the first time a possible involvement of IFN-γ in the acute phase after myocardial infarction (Figure 1).¹² Using IFN-γ reporter mice, the authors report cytokine release from CD4 and CD8 T lymphocytes and natural killer cells in infarcted hearts. In conditional knockout mice which lack the IFN-γ-receptor in myeloid cells including cardiac macrophages, the authors observed decreased accumulation of myeloid cells in infarcted cardiac tissue alongside with impaired cardiac function. Using IFN-γ knockout mice, the authors found reduced chemokine levels accompanied by diminished cardiac myeloid cell accumulation after myocardial infarction. Again, impaired myeloid cell infiltration into injured myocardium associated with reduced left ventricular function. To explore this finding in more detail, Finger et al. applied an antibody mediated neutrophil depletion strategy which led to decreased monocyte levels and impaired cardiac function after myocardial infarction. Mechanistically, neutrophil-derived cathelicidin directed monocyte recruitment to injury, as determined in cathelicidin-knockout mice. These observations are in line with previous studies demonstrating the relevance of an adequate immune response for optimal recovery after myocardial infarction.¹³ Furthermore, the experiments emphasize the importance of neutrophil-directed monocyte migration.^14,15 This study suggests an intriguing, recently unknown beneficial function of IFN-γ in myocardial infarction’s acute phase. Lymphocyte and natural killer cell derived IFN-γ may activate cardiac macrophages, which orchestrate neutrophil recruitment into ischaemic myocardium needed for the aftermath clean-up. IFN-γ deficiency hampers required repair mechanisms. Future studies should address the question which factors trigger IFN-γ release from source cells. Further, it needs to be elucidated whether cardiac macrophages which dominate the heart’s resident leucocyte population in steady state, are causally involved in IFN-γ elicited neutrophil recruitment. In light of recently discovered cardiac macrophage subsets which exacerbate inflammation after myocardial infarction via type 1 IFN signalling, the proposed opposing function of IFN-γ deserves further attention.⁷ While unbridled inflammation may destruct parenchymal tissue in close proximity, insufficient inflammation may impede proper healing and result in secondary necrosis, suggesting a ‘therapeutic inflammatory corridor’ exists in which ideal tissue repair is feasible. Harnessing interferons’ beneficial effects while inhibiting detrimental side-effects in cardiovascular disease should be explored, particularly in the light of existing clinical applications such as in oncology, multiple sclerosis, or viral hepatitis.¹⁶ Studies of IFNs in humans with acute MI are an important next step, for instance exploring if IFN-γ levels associate with outcomes such as post-MI heart failure. In summary, this study by Finger et al. highlights the role of IFN-γ in myocardial ischaemia and proposes a beneficial role of type 2 IFNs in sterile inflammation after myocardial infarction.

Figure 1.

Proposed mechanism of interferon-γ directed myeloid cell response after myocardial infarction. T lymphocytes and natural killer cells release IFN-γ after myocardial infarction. IFN-γ activates tissue resident cardiac macrophages via IFN-γ-receptor. Macrophages release chemokines promoting neutrophil recruitment. Neutrophil-derived cathelicidin attracts monocytes. Disruption of any of these steps interferes with post-ischaemic immune response and impairs cardiac function.

Conflict of interest: none declared.

The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.

Funding

This work was funded from the National Institutes of Health (HL139598).