TLR7/8 agonist treatment remodels the monocytic population

For quite some time I was trying to put together a post about TLR signaling just to find it very difficult task. I was never really involved in research on innate immunity and as a result I may have oversimplified view on the recognition of conserved molecular patterns. Therefore, despite many interesting publications that I have read recently it was hard to make a decision what to write about. Finally, I have chosen the report describing systemic and local effects of treatment with distinct TLR agonists that are used as adjuvants to boost the immune response. This report is attractive for me because I can learn from it that beside the variety in molecular patterns that are detected, different cellular locations at which the recognition takes place and several downstream signaling pathways which are used to convey activation signals there is yet another layer of complexity pertinent to the innate immunity – altered qualities of response at the systemic level. I am aware that it is probably obvious for somebody in the field.

The link:

http://bloodjournal.hematologylibrary.org/content/119/9/2044.abstract

Authors employ rhesus macaques to examine how TLR-based adjuvants may predispose the overall immune activation at both systemic level (samples collected from blood) and local level (samples collected from draining lymph nodes).  The study uses agonists to TLR4 (MPL), TLR7/8 (R-848) and TLR9 (CpG-ODN) and documents multiple parameters of ensuing immune response. These parameters include blood neutrophils and PMBC levels as well as kinetics of different monocytes subsets both in the blood and in local lymph nodes. Apart from that investigators check the frequency and activation status of dendritic cells (either of myeloid or plasmacytoid origin) and systemic levels of inflammatory cytokines.  Additionally, the study contains transcriptional signatures derived from PMBC and lymph node cells with genes that belong to several classes like adhesion, chemokines, interferon signature or complement.

The data have quite broad scope and I am not going to discuss every result that authors have obtained. The one particular observation, however, I find quite intriguing. As you can probably guess, TLR7/8 agonist stimulates rapid and transient up-regulation of inflammatory cytokines in the blood (IFN-α, IP-10, IL-6, IFN-γ and IL-1Ra) whereas other agonists have much less pronounced effect. This TLR7/8-specific effect appears to be followed by complete remodeling of blood monocytes subsets. Authors dissect circulating monocytes into three classes: classical (CD14+CDCD16), intermediate (CD14+CD16+) and non-classical (CD14dimCD16++). On TLR7/8 agonist treatment there is dramatic but reversible increase in both intermediate and non-classical subsets which normally represent minority of blood monocytes. Some remodeling (but much less prominent) is also documented for TLR9 agonist while TLR4 agonist mobilizes only the classical population.

Primate CD14dim monocytes display excellent crawling and tissue retention capabilities.  These cells have been suggested to become activated by autoimmune complexes and thus contribute to pathology development in lupus. It is also known that signaling through TLRs recognizing nucleic acids (especially TLR7 signaling since TLR9 may have in fact the protective effect) can be involved in the tolerance breach through variety of mechanisms. This publication shows that the significant remodeling of monocyte population on TLR7/8 agonist treatment is reversible. What is the mechanism responsible for return to monocyte homeostasis after receiving activation signals? May this return ability be disturbed in lupus or other autoimmune diseases?

Kwissa, M., Nakaya, H., Oluoch, H., & Pulendran, B. (2012). Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates Blood, 119 (9), 2044-2055 DOI: 10.1182/blood-2011-10-388579