Impact of age and sex on myelopoiesis and inflammation during myocardial infarction

Abstract

Of all the different risk factors known to cause cardiovascular disease (CVD), age and sex are considered to play a crucial role. Aging follows a continuum from birth to death, and therefore it inevitably acts as a risk for CVD. Along with age, sex differences have also been shown to demonstrate variations in immune system responses to pathological insults. It has been widely perceived that females are protected against myocardial infarction (MI) and the protection is quite apparent in young vs. old women. Acute MI leads to changes in the population of myeloid and lymphoid cells at the injury site with myeloid bias being observed in the initial inflammation and the lymphoid in the late-resolution phases of the pathology. Multiple evidence demonstrates that aging enhances damage to various cellular processes through inflamm-aging, an inflammatory process identified to increase pro-inflammatory markers in circulation and tissues. Following MI, marked changes were observed in different sub-sets of major myeloid cell types viz., neutrophils, monocytes, and macrophages. There is a paucity of information regarding the tissue and site-specific functions of these sub-sets. In this review, we highlight the importance of age and sex as crucial risk factors by discussing their role during MI-induced myelopoiesis while emphasizing the current status of myeloid cell sub-sets. We further put forth the need for designing and executing age and sex interaction studies aimed to determine the appropriate age and sex to develop personalized therapeutic strategies post-MI.

Keywords: Age; Immunity; Myelopoiesis; Myocardial infarction; Sex.

Fig. 1.. Conceptual framework of sex-based interactions on aging with respect to MI.

Differences in age (young, adult, and aged) manifest with changes in activities of sex-specific chromosomes and hormones. These changes lead to aging differences at three different hierarchal levels; with first being molecular and cellular, second being organ and its functional, and the last at the whole organismal level. Cells that are key to myelopoiesis viz., myeloblasts, neutrophils, monocytes, and macrophages are those majorly affected at molecular and cellular levels in response to MI injury with heart, spleen, and bone marrow at the organ levels. All such changes accompanied with disease associated co-morbidities may finally lead to whole-organismal aging, which involves decreased life and health spans along with development of frailty.

Fig. 2.. Phases involved in MI injury in normal and aged hearts and factors affecting the tissue response.

Post-MI, a normal heart demonstrates an initial inflammation phase characterized with different myeloid cells such as N1 neutrophils, Ly6C^hi monocytes, and M1 macrophages followed by a resolution phase, where neutrophils are N2, monocytes are Ly6C^lo, and macrophages are M2 (further sub-divided as M2a, M2b, and M2c and represented by three different colors). Myeloid cells resulted from myelopoiesis in bone marrow switch from pro-inflammatory to anti-inflammatory phenotype during transition from inflammation to resolution phases of injury. While in aged hearts, myelopoiesis gets enhanced due to feed-back loops thereby enriching inflammatory cytokines because of inflamm-aging and MI exacerbates the underlying tissue and systemic inflammation. This may result in delay of tissue repair due to differences in the rate and extent of myeloid cell phenotypic switch. This delayed may be further impacted with presence of aging associated factors like clonal hematopoiesis (CH) and mosaic loss of Y-chromosome (mLOR). Dotted arrows indicate the necessity for deep phenotyping of the cellular switches both between aged and normal hearts focusing on different myeloid cell sub-sets in future. Circular arrow indicates feed-back loops.

Fig. 3.. Considerations for designing age and sex interaction studies.

Three different disease relevant ages (young, adult, and aged) and both sexes form the pillars while designing interaction studies. Clonal hematopoiesis (CH) in both sexes, alterations in Y-chromosomal activities in males as well as menopause in females can act as key factors while stratifying different experimental groups. Males with changes (decreased or complete loss) in Y-chromosomal activity (LOY) can be further classified based on whether they show CH. While in case of females, both pre-menopausal (P) and menopausal (M) stages shall be further stratified based on the presence or absence of CH. The complexity of the stratification in males may further depend on the extent or percent (%) Y-Chromosomal loss (LOR). In case of females, menopause associated other complexities may also take participation in designing groups. LOY and N refer to loss of Y-Chromosomal activity and normal Y-chromosomal activities, respectively. Y chromosomes in both N and LOR conditions were represented by different colors in the figure.