In our study, we compared the polarisation of AM isolated from human volunteers from distinct geographical locations, UK and Malawi. We report that in healthy human pulmonary mucosa, AM adopt a hybrid phenotype, which shares features of both M1 (CD80, CD86, CD64) and M2 (CD206 and CD163) polarized macrophages. The same phenotype has been previously reported on the decidual macrophages (resident macrophages of the uterine lining), which exhibit characteristics of both pro-inflammatory and tolerogenic macrophages [
11].
We also found that nasal pneumococcal colonization, even though it alters CD4
+ T cell responses in the alveoli [
9], does not alter the expression of key M1 and M2 polarization markers on the surface of AM. This leads to the speculation that a nasal pneumococcal exposure episode is either incompetent to modulate AM polarization or its effect is transient and quickly irreversible due to macrophages high plasticity [
4]. By contrast, chronic HIV infection did affect the expression of CD163 on the M1-like AM subset (CD206
loCD86
hi), with a lower expression of CD163 observed in HIV-infected individuals than HIV-uninfected controls. This finding is intriguing and may be due to active HIV infection of this alveolar macrophage subset [
12] which has been shown to strongly repress CD163 expression on infected-macrophages [
13]. Furthermore, CD163 is shed during activation as soluble CD163 (sCD163) [
14] and this might in part explain the reduction of CD163 on the surface M1-like AM in HIV-infected individuals. However, even with in vivo exposure to pneumococci or HIV, the CD206
hiCD86
hi AM subset remained the major population, and this ascertains the stability of this phenotype.
Our data provides strong evidence suggesting that not all macrophages fall into M1 and M2 subsets. The major AM population in steady state expresses a duo M1/M2 phenotype. This phenotype is present in individuals from two distinct geographical location and is stable even after exposure to stimuli known to alter the alveolar environment. This is consistent with recent call for a rethink of the M1/M2 macrophage paradigm [
5]. It is possible that the lack of stark polarisation is helpful in maintaining a healthy balance between immune tolerance and protective immunity in the alveolar space. However, whether other tissue macrophages, beyond decidual and alveolar macrophages, exhibit similar phenotypes in vivo warrants further investigation.