Credit: CORBIS

Inflammation that is induced by microorganisms is marked by the rapid recruitment of innate immune cells to the infected tissues. By contrast, a study published in Science now shows that helminth-induced tissue inflammation (which is associated with interleukin-4 (IL-4) production) is not associated with the recruitment of monocytes and macrophages, but depends on the proliferation of tissue-resident macrophages.

First, Jenkins et al. observed that although few monocytes are recruited to the pleural cavity following infection with the parasite Litomosoides sigmodontis, macrophages steadily accumulate. Second, these macrophages shared the F4/80hi phenotype of tissue-resident macrophages and expressed proliferation markers. Third, deletion of blood monocytes and macrophages did not affect the increasing numbers of pleural cavity macrophages in response to L. sigmodontis infection. This suggested that helminth infection induces the proliferation of tissue-resident macrophages rather than the recruitment of blood monocytes.

So, how is the proliferation of tissue macrophages induced? IL-4 is produced by innate immune cells and T helper 2 cells during helminth-induced inflammation and has been associated with the accumulation and alternative activation of macrophages. Interestingly, tissue-resident macrophages proliferated less in L. sigmodontis-infected Il4−/− mice, whereas administration of IL-4 to wild-type mice induced the expansion of populations of peritoneal and pleural macrophages, as well as of Kupffer cells. Thus, IL-4 induces macrophage proliferation in the tissues.

Next, mixed bone marrow chimaeras were generated, in which pleural macrophages were protected from deletion and were therefore of recipient origin. Following administration of IL-4 or L. sigmodontis to these chimaeras, recipient-derived pleural macrophage populations expanded, whereas donor macrophages (which were present in the blood) remained absent from the pleural cavity. This confirmed that IL-4 induces the proliferation of tissue-resident macrophages, and not the recruitment of blood macrophages.

Finally, analyses of mice treated with thioglycollate (which induces macrophage migration to the peritoneal cavity) and IL-4 showed that IL-4 can drive the proliferation and alternative activation of recruited macrophages in the tissue.

So, parasitic infections and possibly allergic responses, which both induce IL-4 production, do not initiate rapid monocyte recruitment, but instead cause the progressive IL-4-driven expansion of tissue-resident macrophage populations. However, in the presence of additional pro-inflammatory stimuli that induce monocyte recruitment, IL-4 drives the proliferation and alternative activation of the recruited cells.