Research Article: Phenotypes of macrophages present in the intestine are impacted by stage of disease in cattle naturally infected with Mycobacterium avium subsp. paratuberculosis

Date Published: May 23, 2019

Publisher: Public Library of Science

Author(s): Caitlin J. Jenvey, Adrienne L. Shircliff, John P. Bannantine, Judith R. Stabel, Yung-Fu Chang.


Macrophages play an important role in the host immune response to Mycobacterium avium subsp. paratuberculosis (MAP) infection, however, MAP is able to disrupt normal macrophage functions to avoid destruction. It is unclear whether the phenotypes of macrophages present in the target tissue play a role in the inability to clear MAP infection. The aim of this study was to identify macrophage phenotypes (host defense or resolution and repair) present within the bovine ileum of naturally infected cattle, as well as to ascertain abundance of each macrophage phenotype present during different stages of MAP infection. Immunofluorescent (IF) labeling was performed on frozen bovine mid-ileal tissue sections collected from 28 Holstein dairy cows. Comprehensive IF staining for cytokines, such as IFN-γ, IL-1Ra, IL-1β, IL-10, TGF-β, TNF-α, and uNOS, along with markers such as CD163, CD206, and TLR4, served to define the macrophage phenotypes. Overall, cows in the clinical stage of disease demonstrated significantly higher numbers of resolution and repair macrophages and lower numbers of host defense macrophages in the ileal tissue. Interestingly, subclinically affected cows with asymptomatic disease had a nearly equal ratio of host defense and resolution and repair macrophage phenotypes, whereas macrophage phenotype was skewed to a host defense macrophage in the tissues of the control noninfected cows. The preponderance of M2-like resolution and repair phenotype for macrophages in the tissues of cows with clinical disease would explain why the host fails to control and/or clear the infection, leading to a higher MAP burden. The results of the current study offer insight into the disparate macrophage phenotypes present in the bovine ileum during different stages of infection.

Partial Text

Macrophages play an important role in the host immune response to infection with bacterial pathogens. In particular, Mycobacterium avium subsp. paratuberculosis (MAP), an intracellular pathogen that causes enteritis in ruminants, is engulfed by intestinal macrophages as part of the initial response to infection. The ability of macrophages to destroy the invading pathogen is a critical component of host defense and determines whether the host will clear the infection or eventually succumb to clinical disease. Macrophages may be categorized as either classically activated (M1) or alternatively activated (M2). More definitively, the M1 macrophage encompasses a pro-inflammatory host defense phenotype, whereas M2 macrophages embody both wound-healing (tissue repair) and regulatory phenotypic functions [1] Polarization of macrophages between phenotypes is a dynamic process, with the dominance of a phenotype dependent upon the presence and persistence of stimuli [1–3] Indeed, a plasticity of macrophage phenotypes exists during the infectious process with heterogeneous populations of macrophages observed in mycobacterial infections [4,5]. Furthermore, it is suggested that mycobacteria may be involved in selective recruitment of macrophages [4], as well as inhibition of macrophage inflammatory response [6] that enable them to survive in the host.

Macrophages are key phagocytic cells in the host response against infection with Mycobacterium avium subsp. paratuberculosis (MAP). In addition to the gastrointestinal system (GI) being the largest reservoir of macrophages in the body, the small intestine is the main gateway for MAP to enter the host. The role of intestinal macrophages in MAP infection is to kill the intracellular pathogen and to regulate concomitant inflammatory responses, however, MAP has developed strategies to disrupt the function and responsiveness of the macrophage. (5, 6)

In summary, the current study utilized immunofluorescence to identify macrophage phenotypes present in the mid ileum of cattle naturally infected with MAP. Additionally, the current study was also able to ascertain differences in numbers of macrophage phenotypes between different disease states, as well as relationships between macrophage phenotypes and local cytokine production. Clinical cows demonstrated significantly higher numbers of CD163+ and significantly lower numbers of CD206+ macrophages, although both markers are associated with M2-Like macrophages. Overall, clinical cows demonstrated significantly lower total numbers of macrophages with a host defense phenotype when compared to both subclinical cows and uninfected control cows. Additionally, subclinincal cows demonstrated a balance of host defense and resolution and repair phenotype macrophages, compared to dominant host defense and resolution and repair macrophage phenotypes in control and clinical cows, respectively.




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