Myocardial infarction (MI) is one of the leading causes of death worldwide and inflammation is a key driver. Therapeutic options to specifically address the inflammatory response in MI are lacking.

Macrophage subtypes have pro-inflammatory, but also tissue-regenerative functions across the different phases of MI. Macrophage activation is classically driven by pattern recognition receptors that recognize damage or pathogen-associated molecular patterns. Recent evidence implied a novel pathway in macrophage activation. Olfactory receptor 2 (OLFR2), a receptor involved in mediating the sense of smelling and activated by the saturated fatty aldehyde octanal, is ectopically expressed in vascular macrophages . OLFR2 activated macrophages and aggravated atherosclerosis, whereas the absence of OLFR2 attenuated atherosclerosis and macrophage activation. The role of OLFR2 on cardiac macrophages and myocardial infarction are unknown.

To investigate whether OLFR2 is expressed in hearts after MI, cardiac tissue sections were analyzed by immunofluorescence and RNA in situ hybridization (RNAscope). OLFR2 expression was detected in cardiac macrophages on day 21 and 28 post-MI and in mice treated with octanal post-MI on day 7. Treatment post-MI with the OLFR2 antagonist citral reduced Olfr2 expression.

To understand the therapeutic potential of Olfr2 modulation post-MI, we induced MI surgically by ischemia reperfusion (I / R) in 12-week-old, male C57BL / 6J followed by intraperitoneal injections of vehicle, citral, or octanal for 7 days. Cardiac function was monitored by echocardiography on baseline, day 3, and day 7 post-MI. Mice treated with citral showed increased ejection fraction (46.82% ± 5.26%) in comparison to vehicle controls (36.16% ± 9.77%) or octanal-treated mice (28.78% ± 6.11%) post-MI. Infarct size, determined by Evan's blue and TTC staining on day 7 post-MI, was increased in octanal-treated mice (75.3% ± 2.6%) and decreased in citral-treated mice (53.77% ± 9.75%) compared to vehicle controls ( 61.33%± 12.96%).

To further test how octanal and OLFR2-signaling might affect macrophage responses, bone marrow-derived macrophages (BMDM) were generated from wildtype and OLFR2-deficient mice and stimulated with or without LPS and octanal or citral. We confirmed significantly increased pro-inflammatory cytokine (eg TNF, IL-1) production in supernatants from LPS and octanal stimulated BMDMs, whereas OLFR2-deficiency or treatment with only LPS kept cytokine production at a basal level. Furthermore, LPS and octanal treatment inhibited efferocytotic capacity of BMDMs. Ongoing analysis investigates the effect of OLFR2-deficiency on macrophage and cardiac function in MI.

In conclusion, our data suggests that OLFR2 induces a pro-inflammatory macrophage phenotype and worsens post-MI cardiac function. OLFR2 might be a novel therapeutic target to control the inflammatory response in MI.