Aged neutrophils accumulate in lymphoid tissues from healthy elderly mice and infiltrate T‐ and B‐cell zones

Abstract

The average age of the human population is rising, leading to an increasing burden of age-related diseases, including increased susceptibility to infection. However, immune function can decrease with age which could impact on processes that require a functional immune system. Aging is also characterized by chronic low-grade inflammation which could further impact immune cell function. While changes to neutrophils in blood during aging have been described, little is known in aging lymphoid organs. This study used female C57BL/6J mice comparing bone marrow (BM), spleen and lymph nodes from young mice aged 2-3 months (equivalent to 18 human years) with healthy elderly mice aged 22-24 months (equivalent to 60-70 human years). Neutrophil proportions increased in BM and secondary lymphoid organs of elderly mice relative to their younger counterparts and presented an atypical phenotype. Interestingly, neutrophils from elderly spleen and lymph nodes were long lived (with decreased apoptosis via Annexin V staining and increased proportion of BrdU mature cells) with splenic neutrophils also demonstrating a hypersegmented morphology. Furthermore, splenic neutrophils of elderly mice expressed a mixed phenotype with increased expression of activation markers, CD11b and ICAM-1, increased proinflammatory TNFα, yet increased anti-inflammatory transforming growth factor-beta. Elderly splenic architecture was compromised, as the marginal zone (required for clearing infections) was contracted. Moreover, neutrophils from elderly but not young mice accumulated in lymph node and splenic T- and B-cell zones. Overall, the expansion of functionally compromised neutrophils could contribute to increased susceptibility to infection observed in the elderly.

Neutrophil trafficking to lymphoid tissues: physiological and pathological implications

“…Accordingly, in aged mice neutrophils have been detected in high numbers in both T‐cell and B‐cell areas of the secondary lymphoid organs (i.e. LNs and spleen) . The increased neutrophil trafficking to lymphoid organs was associated with enhanced life‐span of the infiltrated neutrophils and their altered phenotype.…”

“…At present it is unclear what the role of these neutrophils is, but it is speculated that the atypical phenotype of lymphoid organ neutrophils could contribute to ageing‐associated dysregulation of normal adaptive immune responses, e.g. in infections .…”

Recent advances on the crosstalk between neutrophils and B or T lymphocytes

“…For example, human splenic neutrophils were shown to lose their selective perifollicular topography, and to extensively infiltrate the follicular mantle and germinal centre areas of splenic follicles, under systemic inflammatory or infectious disorders . Similarly, in the past few years, several studies performed in immunized or infected mice, or even in healthy elderly mice, have demonstrated that neutrophils can actually accumulate in the B‐cell zones as a consequence of the disruption of the splenic microanatomy and lymph node structure . For instance, a significant neutrophil influx was observed in the B‐cell area of draining lymph nodes after 7 days post‐immunization in a model of adjuvant‐induced emergency granulopoiesis in neutropenic mice .…”

Unrestrained Gαi2Signaling Disrupts Normal Neutrophil Trafficking, Aging, and Clearance

“…Higher magnification inserts demonstrate the infiltration of G184S neutrophils into the white pulp. Normally, in young mice neutrophils do not enter the white pulp or lymph node follicles (Kamenyeva et al, 2015;Tomay et al, 2018). As mice age, rare neutrophils can be found in the white pulp, and infection or LPS challenge can also cause neutrophils to enter the white pulp or lymph node follicles (Bronte and Pittet, 2013;Kamenyeva et al, 2015).…”